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Jones DC, Irving L, Dudley R, Blümli S, Wolny M, Chatzopoulou EI, Pryts S, Ahuja S, Rees DG, Sandercock AM, Rajan S, Varkey R, Kierny M, Kayserian A, Mulgrew K, Bowyer G, Songvilay S, Bienkowska K, Glover MS, Hess S, Dovedi SJ, Wilkinson RW, Arnaldez F, Cobbold M. LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity. J Immunother Cancer 2025; 13:e010012. [PMID: 40246582 PMCID: PMC12007065 DOI: 10.1136/jitc-2024-010012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 03/16/2025] [Indexed: 04/19/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype. METHODS Anti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells. RESULTS In preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models. CONCLUSIONS These findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.
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Affiliation(s)
- Des C Jones
- ICC, Early Oncology R&D, AstraZeneca, Cambridge, UK
- Immunocore Ltd, Abingdon, UK
| | | | | | | | - Marcin Wolny
- Biologics Engineering, AstraZeneca, Cambridge, UK
| | | | - Stacy Pryts
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Shreya Ahuja
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | - Saravanan Rajan
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | - Reena Varkey
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | - Michael Kierny
- Biologics Engineering, AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Kathy Mulgrew
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | | | | | - Matthew S Glover
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | - Sonja Hess
- Dynamic Omics, CGR, Discovery Sciences, R&D, AstraZeneca, Gaithersburg, Maryland, USA
| | | | - Robert W Wilkinson
- ICC, Early Oncology R&D, AstraZeneca, Cambridge, UK
- Immunocore Ltd, Abingdon, UK
| | | | - Mark Cobbold
- ICC, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA
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Cao M, Luan J, Zhai C, Liu H, Zhang Z, Guo N. Targeting leukocyte immunoglobulin‑like receptor B2 in the tumor microenvironment: A new treatment prospect for solid tumors (Review). Oncol Lett 2025; 29:181. [PMID: 39990807 PMCID: PMC11843431 DOI: 10.3892/ol.2025.14927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 01/21/2025] [Indexed: 02/25/2025] Open
Abstract
Leukocyte immunoglobulin-like receptor B2 (LILRB2) functions as an immunosuppressive receptor that has a prominent role in immune regulation. The expression of LILRB2 is higher in a variety of solid malignant tumors compared with that in corresponding normal tissues. LILRB2 can be expressed in tumor cells and tumor stromal cells within the tumor microenvironment. Upregulation of LILRB2 in tumors is significantly associated with a poorer tumor phenotype, increased tolerance to certain therapeutic drugs, tumor immune escape and shorter patient overall survival time. Therefore, LILRB2 can be utilized as a novel biomarker to predict the prognosis of patients with solid malignant tumors, and targeting LILRB2 may be an effective strategy for targeted cancer therapy. The present review provides a general overview of the role and mechanisms of LILRB2 in the microenvironment of solid tumors, and emphasizes the significance of targeting LILRB2 as a promising approach for tumor-specific therapy.
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Affiliation(s)
- Meng Cao
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Jing Luan
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Cui Zhai
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Huan Liu
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Zhenhao Zhang
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Na Guo
- Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
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Wang L, Wu Q, Zhang ZW, Zhang H, Jin H, Zhou XL, Liu JY, Li D, Liu Y, Fan ZS. Colony-stimulating factor 3 and its receptor promote leukocyte immunoglobulin-like receptor B2 expression and ligands in gastric cancer. World J Gastrointest Oncol 2025; 17:97858. [PMID: 39958563 PMCID: PMC11756009 DOI: 10.4251/wjgo.v17.i2.97858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/29/2024] [Accepted: 11/08/2024] [Indexed: 01/18/2025] Open
Abstract
BACKGROUND Colony-stimulating factor 3 (CSF3) and its receptor (CSF3R) are known to promote gastric cancer (GC) growth and metastasis. However, their effects on the immune microenvironment remain unclear. Our analysis indicated a potential link between CSF3R expression and the immunosuppressive receptor leukocyte immunoglobulin-like receptor B2 (LILRB2) in GC. We hypothesized that CSF3/CSF3R may regulate LILRB2 and its ligands, angiopoietin-like protein 2 (ANGPTL2) and human leukocyte antigen-G (HLA-G), contributing to immunosuppression. AIM To investigate the relationship between CSF3/CSF3R and LILRB2, as well as its ligands ANGPTL2 and HLA-G, in GC. METHODS Transcriptome sequencing data from The Cancer Genome Atlas were analyzed, stratifying patients by CSF3R expression. Differentially expressed genes and immune checkpoints were evaluated. Immunohistochemistry (IHC) was performed on GC tissues. Correlation analyses of CSF3R, LILRB2, ANGPTL2, and HLA-G were conducted using The Cancer Genome Atlas data and IHC results. GC cells were treated with CSF3, and expression levels of LILRB2, ANGPTL2, and HLA-G were measured by quantitative reverse transcriptase-polymerase chain reaction and western blotting. RESULTS Among 122 upregulated genes in high CSF3R expression groups, LILRB2 showed the most significant increase. IHC results indicated high expression of LILRB2 (63.0%), ANGPTL2 (56.5%), and HLA-G (73.9%) in GC tissues. Strong positive correlations existed between CSF3R and LILRB2, ANGPTL2, and HLA-G mRNA levels (P < 0.001). IHC confirmed positive correlations between CSF3R and LILRB2 (P < 0.001), and HLA-G (P = 0.010), but not ANGPTL2 (P > 0.05). CSF3 increased LILRB2, ANGPTL2, and HLA-G expression in GC cells. Heterogeneous nuclear ribonucleoprotein H1 modulation significantly altered their expression, impacting CSF3's regulatory effects. CONCLUSION The CSF3/CSF3R pathway may contribute to immunosuppression in GC by upregulating LILRB2 and its ligands, with heterogeneous nuclear ribonucleoprotein H1 playing a regulatory role.
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Affiliation(s)
- Long Wang
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Qi Wu
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Zong-Wen Zhang
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Hui Zhang
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Hui Jin
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Xin-Liang Zhou
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Jia-Yin Liu
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Dan Li
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Yan Liu
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
| | - Zhi-Song Fan
- Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China
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Zheng F, Zhang S, Chang AE, Moon JJ, Wicha MS, Wang SX, Chen J, Liu J, Cheng F, Li Q. Breaking Immunosuppression to Enhance Cancer Stem Cell-Targeted Immunotherapy. Int J Biol Sci 2025; 21:1819-1836. [PMID: 39990669 PMCID: PMC11844285 DOI: 10.7150/ijbs.101025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 12/03/2024] [Indexed: 02/25/2025] Open
Abstract
Cancer stem cell (CSC)-targeted immunotherapy has emerged as a novel strategy in cancer treatment in the past decade. However, its efficacy is significantly limited due to the existence of host immune suppressive activity. Specifically, programmed cell death ligand-1 (PD-L1) is overexpressed in CSCs, and PD-L1 overexpressed CSCs create immunosuppressive milieu via interacting with various immune cells in tumor microenvironments (TME). Hence, novel immunotherapeutic strategies targeting CSCs with concurrent immunosuppression interruption will be promising in enhancing anti-CSC effects. These include dendritic cell (DC) and nanodisc (ND)-based vaccines to present CSC antigens in the forms of CSC lysate, CSC-marker proteins, and CSC-derived peptides to induce anti-CSC immunity. In addition, CSC-directed bispecific antibodies (BiAbs) and antibody drug conjugates (ADCs) have been developed to target CSCs effectively. Furthermore, chimeric antigen receptor (CAR)-T cell therapy and natural killer (NK) cell-based therapy targeting CSCs have achieved progress in both solid and hematologic tumors, and inhibition of CSC associated signaling pathways has proven successful. In this review, we aimed to outline the roles and regulatory mechanisms of PD-L1 in the properties of CSCs; the crosstalk between CSCs and immunosuppressive cells in TME, and recent progress and future promises of immunosuppression blockage to enhance CSC-targeted immunotherapy.
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Affiliation(s)
- Fang Zheng
- Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Shan Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Alfred E. Chang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - James J. Moon
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Max S. Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA
| | | | - Junhui Chen
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Jixian Liu
- Peking University Shenzhen Hospital, Shenzhen, China
| | - Fanjun Cheng
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Qiao Li
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
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Wu S, Cao Z, Lu R, Zhang Z, Sethi G, You Y. Interleukin-6 (IL-6)-associated tumor microenvironment remodelling and cancer immunotherapy. Cytokine Growth Factor Rev 2025:S1359-6101(25)00001-2. [PMID: 39828476 DOI: 10.1016/j.cytogfr.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.
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Affiliation(s)
- Songsong Wu
- Department of Radiation Oncology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhumin Cao
- Department of Interventional and Vascular Surgery, The Seventh People's Hospital of Chongqing, Chongqing, China
| | - Rongying Lu
- Samueli School of Engineering, University of California, Irvine, CA, USA
| | - Zhenwang Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, Hubei Province 437100, China.
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | - Yulai You
- Department of Hepatobiliary surgery, Chongqing University Affiliated Jiangjin Central Hospital, Chongqing, China.
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6
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Gilger BC, Hasegawa T, Sutton RB, Bower JJ, Li C, Hirsch ML. A chimeric anti-vascularization immunomodulator prevents high-risk corneal transplantation rejection via ex vivo gene therapy. Mol Ther 2024; 32:4006-4020. [PMID: 39245940 PMCID: PMC11573577 DOI: 10.1016/j.ymthe.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/06/2024] [Accepted: 09/04/2024] [Indexed: 09/10/2024] Open
Abstract
Corneal blindness affects more than 5 million individuals, with over 180,000 corneal transplantations (CTs) performed annually. In high-risk CTs, almost all grafts are rejected within 10 years. Here, we investigated adeno-associated virus (AAV) ex vivo gene therapy to establish immune tolerance in the corneal allograft to prevent high-risk CT rejection. Our previous work has demonstrated that HLA-G contributes to ocular immune privilege by inhibiting both immune cells and neovascularization; however, homodimerization is a rate-limiting step for optimal HLA-G function. Therefore, a chimeric protein called single-chain immunomodulator (scIM), was engineered to mimic the native activity of the secreted HLA-G dimer complex and eliminate the need for homodimerization. In a murine corneal burn model, AAV8-scIM significantly reduced corneal vascularization and fibrosis. Next, ex vivo AAV8-scIM gene delivery to corneal allografts was evaluated in a high-risk CT rejection rabbit model. All scIM-treated corneas were well tolerated and transparent after 42 days, while 83% of vehicle-treated corneas were rejected. Histologically, AAV-scIM-treated corneas were devoid of immune cell infiltration and vascularization, with minimal fibrosis at the host-graft interface. The data collectively demonstrate that scIM gene therapy prevents corneal neovascularization, reduces trauma-induced corneal fibrosis, and prevents allogeneic CT rejection in a high-risk large animal model.
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Affiliation(s)
- Brian C Gilger
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27607, USA; Bedrock Therapeutics, Raleigh, NC 27613, USA
| | - Tomoko Hasegawa
- Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - R Bryan Sutton
- Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Bedrock Therapeutics, Raleigh, NC 27613, USA
| | - Jacquelyn J Bower
- Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA
| | - Chengwen Li
- Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bedrock Therapeutics, Raleigh, NC 27613, USA
| | - Matthew L Hirsch
- Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA; Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bedrock Therapeutics, Raleigh, NC 27613, USA.
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7
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Jiang Z, Huang Q, Chang Y, Qiu Y, Cheng H, Yang M, Ruan S, Ji S, Sun J, Wang Z, Xu S, Liang R, Dai X, Wu K, Li B, Li D, Zhao H. LILRB2 promotes immune escape in breast cancer cells via enhanced HLA-A degradation. Cell Oncol (Dordr) 2024; 47:1679-1696. [PMID: 38656573 DOI: 10.1007/s13402-024-00947-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2024] [Indexed: 04/26/2024] Open
Abstract
PURPOSE Increased expression of leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is associated with immune evasion in breast cancer (BC). The aim of this study to elucidate the role of LILRB2 in BC progression. METHODS LILRB2 expression in tumor tissues was detected by immunohistochemical staining. Human leukocyte antigen A (HLA-A) expression in BC cells was detected by Western blotting, and HLA-A ubiquitination was detected by immunoprecipitation and histidine pulldown assay. An in-situ tumor model was established in nude BALB/c mice to verify the role of LILRB2 in immune escape. Finally, the functions and potential mechanisms of LILRB2 in BC progression were explored using in silico data. RESULTS LILRB2 was upregulated in BC tissues and cells, and correlated positively with poor prognosis. LILRB2 promoted BC progression by downregulating HLA-A expression. Mechanistically, LILRB2 facilitates the ubiquitination and subsequent degradation of HLA-A by promoting the interaction between the ubiquitin ligase membrane-associated ring finger protein 9 (MARCH9) and HLA-A. In syngeneic graft mouse models, LILRB2-expressing BC cells evaded CD8 + T cells and inhibited the secretion of cytokines by the cytotoxic CD8 + T cells. CONCLUSION LILRB2 downregulates HLA-A to promote immune evasion in BC cells and is a promising new target for BC treatment.
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Affiliation(s)
- Zhiyuan Jiang
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qianru Huang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yujie Chang
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiran Qiu
- Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Hao Cheng
- Department of Rheumatism and Immunology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- Center for Cancer Immunology Research, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Mengdi Yang
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shunyi Ruan
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Suyuan Ji
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Sun
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
| | - Zhiyu Wang
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China
| | - Shengyuan Xu
- College of Arts and Science, New York University, New York, USA
| | - Rui Liang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xueyu Dai
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kejin Wu
- Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China.
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Dan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu District, 200025, Shanghai, China.
- Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Hui Zhao
- Department of Internal Oncology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, China.
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Ingraldi AL, Allen T, Tinghitella JN, Merritt WC, Becker T, Tabor AJ. Characterization of Amnion-Derived Membrane for Clinical Wound Applications. Bioengineering (Basel) 2024; 11:953. [PMID: 39451330 PMCID: PMC11504399 DOI: 10.3390/bioengineering11100953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 10/26/2024] Open
Abstract
Human amniotic membrane (hAM), the innermost placental layer, has unique properties that allow for a multitude of clinical applications. It is a common misconception that birth-derived tissue products, such as dual-layered dehydrated amnion-amnion graft (dHAAM), are similar regardless of the manufacturing steps. A commercial dHAAM product, Axolotl Biologix DualGraft™, was assessed for biological and mechanical characteristics. Testing of dHAAM included antimicrobial, cellular biocompatibility, proteomics analysis, suture strength, and tensile, shear, and compressive modulus testing. Results demonstrated that the membrane can be a scaffold for fibroblast growth (cellular biocompatibility), containing an average total of 7678 unique proteins, 82,296 peptides, and 96,808 peptide ion variants that may be antimicrobial. Suture strength results showed an average pull force of 0.2 N per dHAAM sample (equating to a pull strength of 8.5 MPa). Tensile modulus data revealed variation, with wet samples showing 5× lower stiffness than dry samples. The compressive modulus and shear modulus displayed differences between donors (lots). This study emphasizes the need for standardized processing protocols to ensure consistency across dHAAM products and future research to explore comparative analysis with other amniotic membrane products. These findings provide baseline data supporting the potential of amniotic membranes in clinical applications.
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Affiliation(s)
| | - Tim Allen
- Axolotl Biologix, Scottsdale, AZ 85260, USA; (A.L.I.)
| | | | - William C. Merritt
- Mechanical Engineering and Center for Materials Interfaces in Research and Applications (MIRA), Northern Arizona University, Flagstaff, AZ 86011, USA; (W.C.M.)
| | - Timothy Becker
- Mechanical Engineering and Center for Materials Interfaces in Research and Applications (MIRA), Northern Arizona University, Flagstaff, AZ 86011, USA; (W.C.M.)
| | - Aaron J. Tabor
- Axolotl Biologix, Scottsdale, AZ 85260, USA; (A.L.I.)
- Biological Sciences, Northern Arizona University, Flagstaff, AZ 86011, USA;
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9
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Chen X, Yuan M, Zhong T, Wang M, Wu F, Lu J, Sun D, Xiao C, Sun Y, Hu Y, Wu M, Wang L, Yu J, Chen D. LILRB2 inhibition enhances radiation sensitivity in non-small cell lung cancer by attenuating radiation-induced senescence. Cancer Lett 2024; 593:216930. [PMID: 38705566 DOI: 10.1016/j.canlet.2024.216930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/17/2024] [Accepted: 04/29/2024] [Indexed: 05/07/2024]
Abstract
Radiotherapy (RT) in non-small cell lung cancer (NSCLC) triggers cellular senescence, complicating tumor microenvironments and affecting treatment outcomes. This study examines the role of lymphocyte immunoglobulin-like receptor B2 (LILRB2) in modulating RT-induced senescence and radiosensitivity in NSCLC. Through methodologies including irradiation, lentivirus transfection, and various molecular assays, we assessed LILRB2's expression and its impact on cellular senescence levels and tumor cell behaviors. Our findings reveal that RT upregulates LILRB2, facilitating senescence and a senescence-associated secretory phenotype (SASP), which in turn enhances tumor proliferation and resistance to radiation. Importantly, LILRB2 silencing attenuates these effects by inhibiting the JAK2/STAT3 pathway, significantly increasing radiosensitivity in NSCLC models. Clinical data correlate high LILRB2 expression with reduced RT response and poorer prognosis, suggesting LILRB2's pivotal role in RT-induced senescence and its potential as a therapeutic target to improve NSCLC radiosensitivity.
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Affiliation(s)
- Xiaozheng Chen
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Meng Yuan
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Tao Zhong
- Clinical College of Medicine, Jining Medical University, Jining, Shandong, China
| | - Minglei Wang
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Fei Wu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jie Lu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Dongfeng Sun
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Changyan Xiao
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Yuping Sun
- Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yun Hu
- Department of Radiation Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX, USA
| | - Meng Wu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Linlin Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Jinming Yu
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Research Unit of Radiation Oncology, Chinese Academy of Medical Sciences, Jinan, Shandong, China.
| | - Dawei Chen
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Department of Radiation Oncology, Shandong University Cancer Center, Jinan, Shandong, China.
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10
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Khorami-Sarvestani S, Vanaki N, Shojaeian S, Zarnani K, Stensballe A, Jeddi-Tehrani M, Zarnani AH. Placenta: an old organ with new functions. Front Immunol 2024; 15:1385762. [PMID: 38707901 PMCID: PMC11066266 DOI: 10.3389/fimmu.2024.1385762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/08/2024] [Indexed: 05/07/2024] Open
Abstract
The transition from oviparity to viviparity and the establishment of feto-maternal communications introduced the placenta as the major anatomical site to provide nutrients, gases, and hormones to the developing fetus. The placenta has endocrine functions, orchestrates maternal adaptations to pregnancy at different periods of pregnancy, and acts as a selective barrier to minimize exposure of developing fetus to xenobiotics, pathogens, and parasites. Despite the fact that this ancient organ is central for establishment of a normal pregnancy in eutherians, the placenta remains one of the least studied organs. The first step of pregnancy, embryo implantation, is finely regulated by the trophoectoderm, the precursor of all trophoblast cells. There is a bidirectional communication between placenta and endometrium leading to decidualization, a critical step for maintenance of pregnancy. There are three-direction interactions between the placenta, maternal immune cells, and the endometrium for adaptation of endometrial immune system to the allogeneic fetus. While 65% of all systemically expressed human proteins have been found in the placenta tissues, it expresses numerous placenta-specific proteins, whose expression are dramatically changed in gestational diseases and could serve as biomarkers for early detection of gestational diseases. Surprisingly, placentation and carcinogenesis exhibit numerous shared features in metabolism and cell behavior, proteins and molecular signatures, signaling pathways, and tissue microenvironment, which proposes the concept of "cancer as ectopic trophoblastic cells". By extensive researches in this novel field, a handful of cancer biomarkers has been discovered. This review paper, which has been inspired in part by our extensive experiences during the past couple of years, highlights new aspects of placental functions with emphasis on its immunomodulatory role in establishment of a successful pregnancy and on a potential link between placentation and carcinogenesis.
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Affiliation(s)
- Sara Khorami-Sarvestani
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Negar Vanaki
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sorour Shojaeian
- Department of Biochemistry, School of Medical Sciences, Alborz University of Medical Sciences, Karaj, Iran
| | - Kayhan Zarnani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Allan Stensballe
- Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
- Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Mahmood Jeddi-Tehrani
- Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
| | - Amir-Hassan Zarnani
- Reproductive Immunology Research Center, Avicenna Research Institute, ACECR, Tehran, Iran
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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11
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Wang S, Wang J, Xia Y, Zhang L, Jiang Y, Liu M, Gao Q, Zhang C. Harnessing the potential of HLA-G in cancer therapy: advances, challenges, and prospects. J Transl Med 2024; 22:130. [PMID: 38310272 PMCID: PMC10838004 DOI: 10.1186/s12967-024-04938-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/27/2024] [Indexed: 02/05/2024] Open
Abstract
Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer.
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Affiliation(s)
- Siyuan Wang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jiaxin Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Yu Xia
- Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Le Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Yueqiang Jiang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Man Liu
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Qinglei Gao
- Cancer Biology Research Center (Key Laboratory of Chinese Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
| | - Cuntai Zhang
- Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
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12
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Agbakwuru D, Wetzel SA. The Biological Significance of Trogocytosis. Results Probl Cell Differ 2024; 73:87-129. [PMID: 39242376 PMCID: PMC11784324 DOI: 10.1007/978-3-031-62036-2_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/09/2024]
Abstract
Trogocytosis is the intercellular transfer of membrane and membrane-associated proteins between cells. Trogocytosis is an underappreciated phenomenon that has historically routinely been dismissed as an artefact. With a greater understanding of the process and the implications it has on biological systems, trogocytosis has the potential to become a paradigm changer. The presence on a cell of molecules they don't endogenously express can alter the biological activity of the cell and could also lead to the acquisition of new functions. To better appreciate this phenomenon, it is important to understand how these intercellular membrane exchanges influence the function and activity of the donor and the recipient cells. In this chapter, we will examine how the molecules acquired by trogocytosis influence the biology of a variety of systems including mammalian fertilization, treatment of hemolytic disease of the newborn, viral and parasitic infections, cancer immunotherapy, and immune modulation.
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Affiliation(s)
- Deborah Agbakwuru
- Center for Environmental Health Sciences, University of Montana, Missoula, MT, USA
| | - Scott A Wetzel
- Center for Environmental Health Sciences, University of Montana, Missoula, MT, USA.
- Division of Biological Sciences, University of Montana, Missoula, MT, USA.
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13
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Li D, Wang L, Jiang B, Jing Y, Li X. Improving cancer immunotherapy by preventing cancer stem cell and immune cell linking in the tumor microenvironment. Biomed Pharmacother 2024; 170:116043. [PMID: 38128186 DOI: 10.1016/j.biopha.2023.116043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/07/2023] [Accepted: 12/14/2023] [Indexed: 12/23/2023] Open
Abstract
Cancer stem cells are the key link between malignant tumor progression and drug resistance. This cell population has special properties that are different from those of conventional tumor cells, and the role of cancer stem cell-related exosomes in progression of tumor malignancy is becoming increasingly clear. Cancer stem cell-derived exosomes carry a variety of functional molecules involved in regulation of the microenvironment, especially with regard to immune cells, but how these exosomes exert their functions and the specific mechanisms need to be further clarified. Here, we summarize the role of cancer stem cell exosomes in regulating immune cells in detail, aiming to provide new insights for subsequent targeted drug development and clinical strategy formulation.
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Affiliation(s)
- Dongyu Li
- Department of General Surgery & VIP In-Patient Ward, the First Hospital of China Medical University, Liaoning Province 110001, China
| | - Lei Wang
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Liaoning Province 110001, China
| | - Bo Jiang
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Liaoning Province 110001, China
| | - Yuchen Jing
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Liaoning Province 110001, China
| | - Xuan Li
- Department of Vascular and Thyroid Surgery, the First Hospital of China Medical University, Liaoning Province 110001, China.
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Xu M, Cheng Y, Meng R, Yang P, Chen J, Qiao Z, Wu J, Qian K, Li Y, Wang P, Zhou L, Wang T, Sheng D, Zhang Q. Enhancement of Microglia Functions by Developed Nano-Immuno-Synergist to Ameliorate Immunodeficiency for Malignant Glioma Treatment. Adv Healthc Mater 2023; 12:e2301861. [PMID: 37573475 DOI: 10.1002/adhm.202301861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/02/2023] [Indexed: 08/14/2023]
Abstract
Resident microglia are key factors in mediating immunity against brain tumors, but the microglia in malignant glioma are functionally impaired. Little immunotherapy is explored to restore microglial function against glioma. Herein, oleanolic acid (OA) (microglia "restorer") and D PPA-1 peptide (immune checkpoint blockade) are integrated on a nano-immuno-synergist (D PAM@OA) to work coordinately. The self-assembled OA core is coated with macrophage membrane for efficient blood-brain barrier penetration and microglia targeting, on which D PPA-1 peptide is attached via acid-sensitive bonds for specific release in tumor microenvironment. With the enhanced accumulation of the dual drugs in their respective action sites, D PAM@OA effectively promotes the recruitment and activation of effector T cells by inhibiting aberrant activation of Signal transducer and activator of transcription (STAT-3) pathway in microglia, and assists activated effector T cells in killing tumor cells by blocking elevated immune checkpoint proteins in malignant glioma. Eventually, as adjuvant therapy, the rationally designed nano-immuno-synergist hinders malignant glioma progression and recurrence with or without temozolomide. The work demonstrates the feasibility of a nano-formulation for microglia-based immunotherapy, which may provide a new direction for the treatment of brain tumors.
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Affiliation(s)
- Minjun Xu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Yunlong Cheng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Ran Meng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Peng Yang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Jian Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Zhen Qiao
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Jing Wu
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Kang Qian
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Yixian Li
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Pengzhen Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Lingling Zhou
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Tianying Wang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Dongyu Sheng
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
| | - Qizhi Zhang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai, 201203, P. R. China
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15
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Redondo-García S, Barritt C, Papagregoriou C, Yeboah M, Frendeus B, Cragg MS, Roghanian A. Human leukocyte immunoglobulin-like receptors in health and disease. Front Immunol 2023; 14:1282874. [PMID: 38022598 PMCID: PMC10679719 DOI: 10.3389/fimmu.2023.1282874] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 09/20/2023] [Indexed: 12/01/2023] Open
Abstract
Human leukocyte immunoglobulin (Ig)-like receptors (LILR) are a family of 11 innate immunomodulatory receptors, primarily expressed on lymphoid and myeloid cells. LILRs are either activating (LILRA) or inhibitory (LILRB) depending on their associated signalling domains (D). With the exception of the soluble LILRA3, LILRAs mediate immune activation, while LILRB1-5 primarily inhibit immune responses and mediate tolerance. Abnormal expression and function of LILRs is associated with a range of pathologies, including immune insufficiency (infection and malignancy) and overt immune responses (autoimmunity and alloresponses), suggesting LILRs may be excellent candidates for targeted immunotherapies. This review will discuss the biology and clinical relevance of this extensive family of immune receptors and will summarise the recent developments in targeting LILRs in disease settings, such as cancer, with an update on the clinical trials investigating the therapeutic targeting of these receptors.
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Affiliation(s)
- Silvia Redondo-García
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Christopher Barritt
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Lister Department of General Surgery, Glasgow Royal Infirmary, Glasgow, United Kingdom
- School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom
| | - Charys Papagregoriou
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Muchaala Yeboah
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Björn Frendeus
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- BioInvent International AB, Lund, Sweden
| | - Mark S. Cragg
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Ali Roghanian
- Antibody and Vaccine Group, Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
- Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
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16
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Mahanti K, Bhattacharyya S. Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting. Transl Res 2023; 265:S1931-5244(23)00176-7. [PMID: 39491179 DOI: 10.1016/j.trsl.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.
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Affiliation(s)
- Krishna Mahanti
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India
| | - Sankar Bhattacharyya
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India.
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17
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Zhang H, Gao A, Liu Q, Zhang F, Wang S, Chen X, Shi W, Zhang Y, Liu Q, Zheng Y, Sun Y. ILT4 reprograms glucose metabolism to promote tumor progression in triple-negative breast cancer. J Cell Sci 2023; 136:jcs260964. [PMID: 37622462 DOI: 10.1242/jcs.260964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 08/16/2023] [Indexed: 08/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive and poorly treated subtype of breast cancer. Identifying novel drivers and mechanisms for tumor progression is essential for precise targeted therapy of TNBC. Immunoglobulin-like transcript 4 (ILT4; also known as LILRB2) is a classic myeloid suppressor for their activation and immune response. Our recent results found that ILT4 is also highly expressed in lung cancer cells, where it has a role in promoting immune evasion and thus tumor formation. However, the expression and function of ILT4 in breast cancer remains elusive. Here, using our patient cohort and public database analysis, we found that TNBC displayed the most abundant ILT4 expression among all breast cancer subtypes. Functionally, enriched ILT4 promoted TNBC cell proliferation, migration and invasion in vitro, as well as tumor growth and metastasis in vivo. Further mechanistic analysis revealed that ILT4 reprogrammed aerobic glycolysis of tumor cells via AKT-mTOR signaling-mediated glucose transporter 3 (GLUT3; also known as SLC2A3) and pyruvate kinase muscle 2 (PKM2, an isoform encoded by PKM) overexpression. ILT4 inhibition in TNBC reduced tumor progression and GLUT3 and PKM2 expression in vivo. Our study identified a novel driver for TNBC progression and proposed a promising strategy to combat TNBC by targeting ILT4.
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Affiliation(s)
- Haiqin Zhang
- Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, 250013 Shandong, P. R. China
- Department of Oncology, Central hospital affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
- Research Center of Translational Medicine, Laboratory Animal Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
| | - Aiqin Gao
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Shandong First Medical University, Jinan, 250117 Shandong, P. R. China
| | - Qiaohong Liu
- Department of Ultrasound, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
| | - Fang Zhang
- Department of Oncology, Central hospital affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
- Research Center of Translational Medicine, Laboratory Animal Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
| | - Shuyun Wang
- Phase I Clinical Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, P. R. China
| | - Xiaozheng Chen
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, P. R. China
| | - Wenjing Shi
- Jinan Central Hospital, Shandong University, Jinan, 250013 Shandong, P. R. China
| | - Ye Zhang
- Department of Oncology, Jinan Central Hospital, Weifang Medical University, Weifang, 250013 Shandong, P. R. China
| | - Qian Liu
- Department of Oncology, Jinan Central Hospital, Weifang Medical University, Weifang, 250013 Shandong, P. R. China
| | - Yan Zheng
- Research Center of Translational Medicine, Laboratory Animal Center, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013 Shandong, P. R. China
| | - Yuping Sun
- Phase I Clinical Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117 Shandong, P. R. China
- Phase I Clinical Research Center, Shandong University Cancer Center, Shandong Cancer Hospital and Institute, Jinan, 250117 Shandong, P. R. China
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18
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Mejía-Guarnizo LV, Monroy-Camacho PS, Rincón-Rodríguez DE, Rincón-Riveros A, Martinez-Vargas DA, Huertas-Caro CA, Oliveros-Wilches R, Sanchez-Pedraza R, Nuñez-Lemus M, Cristancho-Lievano CF, Castellanos-Moreno AM, Martinez-Correa LM, Rodríguez-García JA. Soluble HLA-G (sHLA-G) measurement might be useful as an early diagnostic biomarker and screening test for gastric cancer. Sci Rep 2023; 13:13119. [PMID: 37573450 PMCID: PMC10423220 DOI: 10.1038/s41598-023-40132-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 08/04/2023] [Indexed: 08/14/2023] Open
Abstract
Gastric cancer (GC) is the fifth most frequent malignancy worldwide and has a high mortality rate related to late diagnosis. Although the gold standard for the GC diagnosis is endoscopy with biopsy, nonetheless, it is not cost-effective and is invasive for the patient. The Human leukocyte antigen G (HLA-G) molecule is a checkpoint of the immune response. Its overexpression in cancer is associated with immune evasion, metastasis, poor prognosis, and lower overall survival. We evaluate the plasma levels of soluble HLA-G, (sHLA-G) in patients with GC and benign gastric pathologies using an ELISA test. A higher concentration of sHLA-G in patients with GC than in those with benign pathologies, higher levels of plasma sHLA-G in women with GC compared with men and significant differences in the sHLA-G levels between the benign gastric pathologies evaluated, was our main findings. As no significant differences were found between the GC assessed stages in our study population, we suggest that sHLA-G is not an adequate marker for staging GC, but it does have diagnostic potential. In addition to providing information on the potential of sHLA-G as a diagnostic marker for GC, our study demonstrate that HLA-G molecules can be found in the membrane of exosomes, which highlights the need to perform studies with a larger number of samples to explore the functional implications of HLA-G positive exosomes in the context of gastric cancer, and to determine the clinical significance and possible applications of these findings in the development of non-invasive diagnostic methods.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Marcela Nuñez-Lemus
- Research Support and Monitoring Group, Instituto Nacional de Cancerología, Bogotá, Colombia
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Mao J, Feng Y, Zhu X, Ma F. The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy. Biomolecules 2023; 13:1213. [PMID: 37627278 PMCID: PMC10452754 DOI: 10.3390/biom13081213] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/01/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical human major histocompatibility complex (MHC-I) molecule with the membrane-bound and soluble types. HLA-G is primarily expressed by extravillous cytotrophoblast cells located at the maternal-fetal interface during pregnancy and is essential in establishing immune tolerance. This review provides a comprehensive understanding of the multiple molecular mechanisms by which HLA-G regulates the immune function of NK cells. It highlights that HLA-G binds to microRNA to suppress NK cell cytotoxicity and stimulate the secretion of growth factors to support fetal growth. The interactions between HLA-G and NK cells also activate senescence signaling, promoting spiral artery remodeling and maintaining the balance of maternal-fetal immune responses. In addition, HLA-G can inhibit the function of decidual T cells, dendritic cells, and macrophages. Overall, the interaction between trophoblast cells and immune cells mediated by HLA-G plays a crucial role in understanding immune regulation at the maternal-fetal interface and offers insights into potential treatments for pregnancy-related diseases.
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Affiliation(s)
- Jia Mao
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, State Key Laboratory of Biotherapy and Cancer Center, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Ying Feng
- Department of Histology, Embryology and Neurobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China;
| | - Xiaofeng Zhu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, State Key Laboratory of Biotherapy and Cancer Center, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Fang Ma
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China;
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
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20
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Xu HH, Xie YY, Jun-Gan, Yang Z, Han QY. Dynamic changes of soluble HLA-G and cytokine plasma levels in cervical cancer patients: potential role in cancer progression and immunotherapy. J Cancer Res Clin Oncol 2023; 149:4195-4204. [PMID: 36053326 PMCID: PMC10349748 DOI: 10.1007/s00432-022-04331-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/24/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE Chronic inflammation has been proven to be an important factor in carcinogenesis. Cytokines are the central mediators in the inflammatory microenvironment, and their release may be influenced by soluble HLA-G (sHLA-G). The aim of this study was to monitor the dynamic process of these soluble factors in patients with cervical cancer at Taizhou Hospital of Zhejiang Province, trying to understand their relationship with diagnosis, treatment, and prognosis. METHODS We quantified plasma levels of sHLA-G and 12 cytokines using ELISA and flow cytometry, respectively, in the peripheral blood of patients with cervical cancer divided into three groups: preoperation, postoperation and clinical relapse. Healthy women were used as the control group. Data were analysed by non-parametric tests, receiver-operating characteristic (ROC) curves, and Kaplan-Meier plotter (log-rank test). RESULTS In this study, our findings showed that preoperation plasma levels of sHLA-G and the cytokines IL-6, IL-10, and IFN-γ in cervical cancer patients had a good discriminatory effect between cervical cancer patients and healthy women. It should be noted that plasma levels of sHLA-G, IL-6, and IL-10 were significantly decreased within 30 days after radical hysterectomy (P < 0.05). A positive correlation was observed between IL-6 and IL-10, IL-8 and IL-17 levels preoperatively. In contrast, sHLA-G levels were negatively correlated with IL-10 but not with other cytokines. An increased survival rate in patients with cervical cancer was associated with IL-5 < 1.70 pg/mL, IL-17 < 2.30 pg/mL, and IFN-α < 2.26 pg/mL preoperatively. In addition, our findings showed that the levels of cytokines IL-6, IL-8, IL-12p70, IL-17, and IFN-γ may be related to 5-year relapse rates and/or the metastasis of cervical cancer. CONCLUSION The current findings enhance our understanding of the dynamic process (preoperation, postoperation and clinical relapse) of sHLA-G and these cytokines in the plasma of patients with cervical cancer from diagnosis to prognosis. These biomarkers may play a potential therapeutic target role of such dynamic changes in the immunotherapy for cervical cancer.
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Affiliation(s)
- Hui-Hui Xu
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China.
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, Zhejiang, People's Republic of China.
| | - You-You Xie
- Radiotherapy Department, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China
| | - Jun-Gan
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China
| | - Zhi Yang
- Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China
| | - Qiu-Yue Han
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, Zhejiang, People's Republic of China
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21
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Parra LM, Sartori BGC, Fernandes DR, Fachin LRV, Nogueira MRS, Belone AFF, Nunes AJF, Souza-Santana FC. HLA-G expression in Merkel cell carcinoma and the correlation with Merkel cell polyomavirus infection. Immunogenetics 2023; 75:81-89. [PMID: 36229691 DOI: 10.1007/s00251-022-01279-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 09/30/2022] [Indexed: 11/05/2022]
Abstract
Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine cutaneous carcinoma with a high mortality rate. The MCC etiology is not fully understood. Merkel cell-associated polyomavirus (MCPyV) was found in MCC patients, indicating a risk factor for the tumor. Caucasian, elderly, and immunocompromised individuals are more likely to develop this tumor. HLA-G consists of a non-classical class I (Ib) HLA molecule with an immunoregulatory function and was associated with tumor escape in different types of tumors, nonetheless, never been studied in MCC. The purpose of this study was to evaluate the HLA-G expression and also to detect the MCPyV in MCC patients and correlate it with the clinical course of the disease. Forty-five MCC patients were included in a retrospective study. Formalin-fixed paraffin-embedded cutaneous skin biopsies were used by immunohistochemistry and RT-PCR to verify the HLA-G expression and MCPyV infection. HLA-G expression was found in 7 (15.6%), while the presence of MCPyV was detected in 28 (62.2%) of the studied patients. No significant association was found between HLA-G expression and MCPyV infection (p = 0.250). The presence of MCPyV was associated with areas of low sunlight exposure (p = 0.042) and the HLA-G expression with progression to death (p = 0.038). HLA-G expression was detected in MCC patients, as well as the MCPyV presence was confirmed. These markers could represent factors with a possible impact on patient survival; however, further studies with a greater number of patients are needed, to better elucidate the possible role in disease progression.
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Affiliation(s)
- L M Parra
- Clinical Laboratory, Amaral Carvalho Hospital-Jaú, Dona Silvéria, 150 - Chácara Braz Miraglia, São Paulo, 17210-070, Brazil.
| | - B G C Sartori
- Molecular Biology Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
| | - D R Fernandes
- Pathological Anatomy Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
| | - L R V Fachin
- Molecular Biology Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
| | - M R S Nogueira
- Biology Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
| | - A F F Belone
- Pathological Anatomy Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
| | - A J F Nunes
- Pathological Anatomy Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
- Pathological Anatomy Department, Amaral Carvalho Hospital, Jaú, São Paulo, Brazil
| | - F C Souza-Santana
- Immunology Laboratory, Lauro de Souza Lima Institute, Bauru, São Paulo, Brazil
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22
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Wu B, Shi X, Jiang M, Liu H. Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment. Mol Cancer 2023; 22:38. [PMID: 36810098 PMCID: PMC9942413 DOI: 10.1186/s12943-023-01748-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/15/2023] [Indexed: 02/24/2023] Open
Abstract
Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.
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Affiliation(s)
- Bo Wu
- grid.459742.90000 0004 1798 5889Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Xiang Shi
- grid.459742.90000 0004 1798 5889Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042 China
| | - Meixi Jiang
- grid.412644.10000 0004 5909 0696Department of Neurology, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032 China
| | - Hongxu Liu
- Department of Thoracic Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China.
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23
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Bassey-Archibong BI, Rajendra Chokshi C, Aghaei N, Kieliszek AM, Tatari N, McKenna D, Singh M, Kalpana Subapanditha M, Parmar A, Mobilio D, Savage N, Lam F, Tokar T, Provias J, Lu Y, Chafe SC, Swanton C, Hynds RE, Venugopal C, Singh SK. An HLA-G/SPAG9/STAT3 axis promotes brain metastases. Proc Natl Acad Sci U S A 2023; 120:e2205247120. [PMID: 36780531 PMCID: PMC9974476 DOI: 10.1073/pnas.2205247120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 09/18/2022] [Indexed: 02/15/2023] Open
Abstract
Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies.
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Affiliation(s)
| | - Chirayu Rajendra Chokshi
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Nikoo Aghaei
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Agata Monika Kieliszek
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Nazanin Tatari
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Dillon McKenna
- Department of Surgery, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Mohini Singh
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | | | - Arun Parmar
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Daniel Mobilio
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Neil Savage
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Fred Lam
- Department of Surgery, Division of Neurosurgery, McMaster University Faculty of Health Sciences, Hamilton General Hospital, Hamilton, ON, L8S 4K1, Canada
| | - Tomas Tokar
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, ON, M5T 2S8, Canada
- Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, M5T 2S8, Canada
| | - John Provias
- Department of Anatomical Pathology (Neuropathology), Hamilton General Hospital, Hamilton, ON, L8L 2X2, Canada
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Yu Lu
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | | | - Charles Swanton
- The Cancer Research UK (CRUK) Lung Cancer Centre of Excellence, University College London (UCL) Cancer Institute, University College London, London, WC1E 6DD, United Kingdom
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, United Kingdom
| | - Robert Edward Hynds
- The Cancer Research UK (CRUK) Lung Cancer Centre of Excellence, University College London (UCL) Cancer Institute, University College London, London, WC1E 6DD, United Kingdom
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, United Kingdom
| | - Chitra Venugopal
- Department of Surgery, McMaster University, Hamilton, ON, L8S 4K1, Canada
| | - Sheila Kumari Singh
- Department of Surgery, McMaster University, Hamilton, ON, L8S 4K1, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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24
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Wang J, Zhao SJ, Wang LL, Lin XX, Mor G, Liao AH. Leukocyte immunoglobulin-like receptor subfamily B: A novel immune checkpoint molecule at the maternal-fetal interface. J Reprod Immunol 2023; 155:103764. [PMID: 36434938 DOI: 10.1016/j.jri.2022.103764] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/22/2022] [Accepted: 11/10/2022] [Indexed: 11/15/2022]
Abstract
Due to their crucial roles in embryo implantation, maternal-fetal tolerance induction, and pregnancy progression, immune checkpoint molecules (ICMs), such as programmed cell death-1, cytotoxic T-lymphocyte antigen 4, and T cell immunoglobulin mucin 3, are considered potential targets for clinical intervention in pregnancy complications. Despite the considerable progress on these molecules, our understanding of ICMs at the maternal-fetal interface is still limited. Identification of alternative and novel ICMs and the combination of multiple ICMs is urgently needed for deeply understanding the mechanism of maternal-fetal tolerance and to discover the causes of pregnancy complications. Leukocyte immunoglobulin-like receptor subfamily B (LILRB) is a novel class of ICMs with strong negative regulatory effects on the immune response. Recent studies have revealed that LILRB is enriched in decidual immune cells and stromal cells at the maternal-fetal interface, which can modulate the biological behavior of immune cells and promote immune tolerance. In this review, we introduce the structural features, expression profiles, ligands, and orthologs of LILRB. In addition, the potential mechanisms and functions mediated by LILRB for sustaining the maternal-fetal tolerance microenvironment, remodeling the uterine spiral artery, and induction of pregnancy immune memory are summarized. We have also provided new suggestions for further understanding the roles of LILRB and potential therapeutic strategies for pregnancy-related diseases.
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Affiliation(s)
- Jing Wang
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Si-Jia Zhao
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Li-Ling Wang
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Xin-Xiu Lin
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Gil Mor
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China; C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA
| | - Ai-Hua Liao
- Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
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25
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HLA-G in asthma and its potential as an effective therapeutic agent. Allergol Immunopathol (Madr) 2023; 51:22-29. [PMID: 36617818 DOI: 10.15586/aei.v51i1.650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/06/2022] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Asthma is a heterogeneous disease. Severity of asthma and sensitivity to medications vary across asthma subtypes. Human leukocyte antigen (HLA)-G has a wide range of functions in normal and pathological physiology. Due to its powerful immune function, HLA-G participates in the pathogenesis of different asthma phenotypes by regulating the activity and function of various immune cells. The mechanism of HLA-G in asthma is not fully clear, and there is no consensus on its mechanism in asthma. Further studies are needed to explore the role of HLA-G in different phenotypes of human asthma. METHODS Observational study. RESULTS HLA-G is an important immunomodulatory factor in asthma. Studies have found different levels of HLA-G in patients with different asthma subtypes and healthy controls, but other studies have come to the opposite conclusion. CONCLUSION We speculate that further study on the mechanism of HLA-G in asthma pheno-types may explain some of the contradictions in current studies. Findings should provide information regarding the potential of HLA-G as a novel target for asthma diagnosis and treatment.
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26
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Liu J, Zhang F, He J, Wang S, Wang L, Li J, Shi W, Han Y, Gao A, Sun Y. Tumor-derived Immunoglobulin-like transcript 4 facilitates angiogenesis of colorectal cancer. Am J Cancer Res 2023; 13:419-435. [PMID: 36895964 PMCID: PMC9989613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/24/2022] [Indexed: 03/11/2023] Open
Abstract
Current anti-angiogenic therapies have changed the paradigm of treating colorectal cancer (CRC) patients with advanced diseases. However, the clinical response rate is still low at less than 10% due largely to complex angiogenic factors released by tumor cells. Exploring novel mechanisms of tumor angiogenesis and identifying alternative targets for combination therapies are therefore essential to effective inhibition of tumor vascularization and CRC development. Immunoglobulin-like transcript 4 (ILT4), initially identified as a suppressor of myeloid cell activity, is enriched in solid tumor cells. ILT4 favors tumor progression by inducing tumor malignant biologies as well as an immunosuppressive microenvironment. However, whether and how tumor-derived ILT4 orchestrates tumor angiogenesis is still undetermined. Here we found that tumor-derived ILT4 was positively correlated with microvessel density in CRC tissues. ILT4 induced the migration and tube formation of HUVECs in vitro and angiogenesis in vivo. Mechanistically, the activation of MAPK/ERK signaling and subsequent up-regulation of vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor 1 (FGF-1) were responsible for ILT4-induced angiogenesis and tumor progression. Importantly, ILT4 inhibition suppressed tumor angiogenesis and enhanced the efficacy of Bevacizumab treatment in CRC. Our study has identified a novel mechanism for ILT4-mediated tumor progression, which signals a new therapeutic target and alternative combination strategies to combat CRC.
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Affiliation(s)
- Jing Liu
- Cheeloo College of Medicine, Shandong University Jinan 250012, Shandong, P. R. China.,Department of Oncology, Affiliated Hospital of Weifang Medical University Weifang 261031, Shandong, P. R. China
| | - Fang Zhang
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University Jinan 250013, Shandong, P. R. China
| | - Jie He
- Department of Oncology, People's Hospital of Zhangqiu District Jinan 250299, Shandong, P. R. China
| | - Shuyun Wang
- Phase I Clinical Study Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science Jinan 250117, Shandong, P. R. China
| | - Leirong Wang
- Phase I Clinical Study Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science Jinan 250117, Shandong, P. R. China
| | - Juan Li
- Department of Oncology, Central Hospital Affiliated to Shandong First Medical University Jinan 250013, Shandong, P. R. China
| | - Wenjing Shi
- Cheeloo College of Medicine, Shandong University Jinan 250012, Shandong, P. R. China
| | - Yali Han
- Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan 250012, Shandong, P. R. China
| | - Aiqin Gao
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University Jinan 250117, Shandong, P. R. China
| | - Yuping Sun
- Phase I Clinical Study Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Science Jinan 250117, Shandong, P. R. China
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27
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Amodio G, Capogrosso P, Pontillo M, Tassara M, Boeri L, Carenzi C, Cignoli D, Ferrara AM, Ramirez GA, Tresoldi C, Locatelli M, Santoleri L, Castagna A, Zangrillo A, De Cobelli F, Tresoldi M, Landoni G, Rovere‐Querini P, Ciceri F, Montorsi F, Salonia A, Gregori S. Combined plasma levels of IL-10 and testosterone, but not soluble HLA-G5, predict the risk of death in COVID-19 patients. Andrology 2023; 11:32-44. [PMID: 36323494 PMCID: PMC9877736 DOI: 10.1111/andr.13334] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/05/2022]
Abstract
BACKGROUND The identification of biomarkers correlated with coronavirus disease 2019 (COVID-19) outcomes is a relevant need for clinical management. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by elevated interleukin (IL)-6, IL-10, HLA-G, and impaired testosterone production. OBJECTIVES We aimed at defining the combined impact of sex hormones, interleukin-10, and HLA-G on COVID-19 pathophysiology and their relationship in male patients. MATERIALS AND METHODS We measured by chemiluminescence immunoassay, electrochemiluminescent assays, and enzyme-linked immunosorbent assay circulating total testosterone, 17β-estradiol (E2 ), IL-10, and -HLAG5 as well as SARS-CoV-2 S1/S2 Immunoglobulin G from 292 healthy controls and 111 COVID-19 patients with different disease severity at hospital admission, and in 53 COVID-19 patients at 7-month follow-up. RESULTS AND DISCUSSION We found significantly higher levels of IL-10, HLA-G, and E2 in COVID-19 patients compared to healthy controls and an inverse correlation between IL-10 and testosterone, with IL-10, progressively increasing and testosterone progressively decreasing with disease severity. This correlation was lost at the 7-month follow-up. The risk of death in COVID-19 patients with low testosterone increased in the presence of high IL-10. A negative correlation between SARS-CoV-2 Immunoglobulin G and HLA-G or IL-10 at hospitalization was observed. At the 7-month follow-up, IL-10 and testosterone normalized, and HLA-G decreased. CONCLUSION Our findings indicate that combined evaluation of IL-10 and testosterone predicts the risk of death in men with COVID-19 and support the hypothesis that IL-10 fails to suppress excessive inflammation by promoting viral spreading.
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Affiliation(s)
- Giada Amodio
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS Ospedale San RaffaeleMilanItaly
| | - Paolo Capogrosso
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly,Department of Urology and AndrologyOspedale di Circolo and Macchi FoundationVareseItaly
| | - Marina Pontillo
- Laboratory Medicine ServiceIRCCS Ospedale San RaffaeleMilanItaly
| | - Michela Tassara
- Laboratory Medicine ServiceIRCCS Ospedale San RaffaeleMilanItaly
| | - Luca Boeri
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly,IRCCS Foundation Ca’ Granda, Maggiore Policlinico Hospital, Department of UrologyUniversity of MilanMilanItaly
| | - Cristina Carenzi
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly
| | - Daniele Cignoli
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly,University Vita‐Salute San RaffaeleMilanItaly
| | - Anna Maria Ferrara
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly
| | - Giuseppe A. Ramirez
- University Vita‐Salute San RaffaeleMilanItaly,Immunology, Rheumatology, Allergology and Rare Diseases UnitIRCCS Ospedale San RaffaeleMilanItaly
| | | | | | - Luca Santoleri
- Immunohematology and Transfusion MedicineIRRCS Ospedale San RaffaeleMilanItaly
| | - Antonella Castagna
- University Vita‐Salute San RaffaeleMilanItaly,Department of Infectious DiseasesIRCCS Ospedale San RaffaeleMilanItaly
| | - Alberto Zangrillo
- University Vita‐Salute San RaffaeleMilanItaly,Anesthesia and Intensive Care DepartmentIRCCS Ospedale San RaffaeleMilanItaly
| | - Francesco De Cobelli
- University Vita‐Salute San RaffaeleMilanItaly,Department of RadiologyIRCCS Ospedale San RaffaeleMilanItaly
| | - Moreno Tresoldi
- General Medicine and Advanced Care UnitIRCCS Ospedale San RaffaeleMilanItaly
| | - Giovanni Landoni
- University Vita‐Salute San RaffaeleMilanItaly,Anesthesia and Intensive Care DepartmentIRCCS Ospedale San RaffaeleMilanItaly
| | - Patrizia Rovere‐Querini
- University Vita‐Salute San RaffaeleMilanItaly,Internal Medicine, Diabetes, and Endocrinology UnitIRCCS San Raffaele Scientific InstituteMilanItaly
| | - Fabio Ciceri
- University Vita‐Salute San RaffaeleMilanItaly,Hematology and Bone Marrow Transplant UnitIRCCS Ospedale San RaffaeleMilanItaly
| | - Francesco Montorsi
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly,University Vita‐Salute San RaffaeleMilanItaly
| | - Andrea Salonia
- Division of Experimental Oncology/Unit of UrologyURI, IRCCS Ospedale San RaffaeleMilanItaly,University Vita‐Salute San RaffaeleMilanItaly
| | - Silvia Gregori
- San Raffaele Telethon Institute for Gene Therapy (SR‐TIGET)IRCCS Ospedale San RaffaeleMilanItaly
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Li S, Wang D, Cheng J, Sun J, Kalvakolanu DV, Zhao X, Wang D, You Y, Zhang L, Yu D. A photodynamically sensitized dendritic cell vaccine that promotes the anti-tumor effects of anti-PD-L1 monoclonal antibody in a murine model of head and neck squamous cell carcinoma. J Transl Med 2022; 20:505. [PMID: 36329529 PMCID: PMC9635135 DOI: 10.1186/s12967-022-03707-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 10/07/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors are promising tools in combating several cancers, including head and neck squamous cell carcinoma (HNSCC). However, a substantial portion of HNSCC patients do not respond to PD-L1 antibody. Here we describe a photodynamic therapeutic (PDT) approach to enhance anti-tumor effects of the anti-PD-L1 antibody. METHODS Phototoxicity of PDT was confirmed using fluorescence microscopy, Cell Counting Kit-8 (CCK-8), Enzyme Linked Immunosorbent Assay (ELISA) and flow cytometry analyses. Phenotypic and functional maturation of immature DCs (imDCs) induced by PDT were measured using flow cytometry and ELISA. A mouse model was established using the HNSCC line, SCC7, and was used to evaluate therapeutic effects of PDT-DC vaccine in facilitating anti-tumor immunity of PD-L1 antibody. RESULTS Immunogenic cell death (ICD) of SCC7 cells was induced by PDT with 0.5 µM of m-THPC and the 5 J/cm2 of light dose. ICD of SCC7 cells stimulated imDCs maturation. In vivo assays suggested that PDT-DC vaccine and anti-PD-L1 mAb synergistically induced anti-tumor immunity and suppressed tumor progression. CONCLUSION PDT-DC vaccine enhances therapeutic effects of PD-L1 antibody, which might provide a novel approach for HNSCC immunotherapy.
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Affiliation(s)
- Shuang Li
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China
| | - Ding Wang
- Key Laboratory of Pathobiology, Department of pathophysiology, College of Basic Medical Sciences, Ministry of Education, Jilin University, 126 Xinmin Street, 130012, Changchun, Jilin, P.R. China
| | - Jinzhang Cheng
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China
| | - Jicheng Sun
- Key Laboratory of Pathobiology, Department of pathophysiology, College of Basic Medical Sciences, Ministry of Education, Jilin University, 126 Xinmin Street, 130012, Changchun, Jilin, P.R. China
| | - Dhan V Kalvakolanu
- Key Laboratory of Pathobiology, Department of pathophysiology, College of Basic Medical Sciences, Ministry of Education, Jilin University, 126 Xinmin Street, 130012, Changchun, Jilin, P.R. China.,Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Maryland School Medicine, Baltimore, MD, USA
| | - Xue Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China
| | - Di Wang
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China
| | - Yunhan You
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China
| | - Ling Zhang
- Key Laboratory of Pathobiology, Department of pathophysiology, College of Basic Medical Sciences, Ministry of Education, Jilin University, 126 Xinmin Street, 130012, Changchun, Jilin, P.R. China.
| | - Dan Yu
- Department of Otolaryngology-Head and Neck Surgery, The Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, 130041, Changchun, Jilin Province, People's Republic of China.
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29
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Dianat-Moghadam H, Mahari A, Salahlou R, Khalili M, Azizi M, Sadeghzadeh H. Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy. Stem Cell Res Ther 2022; 13:150. [PMID: 35395787 PMCID: PMC8994338 DOI: 10.1186/s13287-022-02829-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.
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Affiliation(s)
- Hassan Dianat-Moghadam
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Amir Mahari
- Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR, USA
| | - Reza Salahlou
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mostafa Khalili
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehdi Azizi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hadi Sadeghzadeh
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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30
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Bitsch R, Kurzay A, Özbay Kurt F, De La Torre C, Lasser S, Lepper A, Siebenmorgen A, Müller V, Altevogt P, Utikal J, Umansky V. STAT3 inhibitor Napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice. J Immunother Cancer 2022; 10:jitc-2021-004384. [PMID: 35301236 PMCID: PMC8932276 DOI: 10.1136/jitc-2021-004384] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Background Myeloid-derived suppressor cells (MDSCs) represent a negative prognostic factor in malignant melanoma. These cells are generated under chronic inflammatory conditions typical of cancer. The transcription factor signal transducer and activator of transcription 3 (STAT3) orchestrates MDSC accumulation and acquisition of immunosuppressive properties. Here we studied STAT3 inhibition by Napabucasin as a way to block MDSC accumulation and activity and its potential to treat malignant melanoma. Methods In vitro generated murine MDSC and primary MDSC from melanoma-bearing mice were used to investigate the effects of Napabucasin on MDSC in vitro. The RET transgenic mouse model of malignant melanoma was used to examine Napabucasin therapy efficiency and its underlying mechanisms in vivo. Furthermore, STAT3 activation and its correlation with survival were explored in MDSC from 19 patients with malignant melanoma and human in vitro generated monocytic myeloid-derived suppressor cell (M-MDSC) were used to evaluate the effects of Napabucasin. Results Napabucasin was able to abrogate the capacity of murine MDSC to suppress CD8+ T-cell proliferation. The STAT3 inhibitor induced apoptosis in murine MDSC, significantly increased expression of molecules associated with antigen processing and presentation, as well as slightly decreased expression of immunosuppressive factors on these cells. RET transgenic mice treated with Napabucasin showed prolonged survival accompanied by a strong accumulation of tumor-infiltrating antigen-presenting cells and activation of CD8+ and CD4+ T cells. Interestingly, patients with malignant melanoma with high expression of activated STAT3 in circulating M-MDSC showed significantly worse progression-free survival (PFS) than patients with low levels of activated STAT3. In addition, Napabucasin was able to abrogate suppressive capacity of human in vitro generated M-MDSC. Conclusion Our findings demonstrate that STAT3 inhibitor Napabucasin completely abrogated the immunosuppressive capacity of murine MDSC and human M-MDSC and improved melanoma-bearing mouse survival. Moreover, patients with malignant melanoma with high expression levels of activated STAT3 in M-MDSC displayed shorter PFS, indicating its role as a promising therapeutic target in patients with malignant melanoma and a predictive marker for their clinical outcome.
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Affiliation(s)
- Rebekka Bitsch
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Annina Kurzay
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Feyza Özbay Kurt
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany.,Faculty of Biosciences, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany
| | - Carolina De La Torre
- NGS Core Facility, Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany
| | - Samantha Lasser
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany.,Faculty of Biosciences, Ruprecht-Karl University of Heidelberg, Heidelberg, Germany
| | - Alisa Lepper
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Alina Siebenmorgen
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Verena Müller
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany
| | - Peter Altevogt
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Jochen Utikal
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Viktor Umansky
- Skin Cancer Unit/ Department of Dermatology, Venerology and Allergology, German Cancer Research Center (DKFZ), University Medical Centre Mannheim, Heidelberg, Mannheim, Germany .,Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.,DKFZ-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
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31
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Kim SK, Kwon HE, Jeong KH, Shin MK, Lee MH. Association between exonic polymorphisms of human leukocyte antigen-G gene and non-segmental vitiligo in the Korean population. Indian J Dermatol Venereol Leprol 2022; 88:749-754. [PMID: 35389019 DOI: 10.25259/ijdvl_219_2021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 11/01/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Vitiligo is a pigmentary skin disorder characterised by a chronic and progressive loss of melanocytes. Although several theories have been suggested to the pathogenesis of vitiligo, an autoimmune process leading to melanocyte destruction appears most likely. Human leukocyte antigen-G is a non-classic, major histocompatibility complex Class I molecule that plays an important role in the suppression of the immune response. Several recent studies have provided evidences that polymorphisms in the human leukocyte antigen-G gene might be related with autoimmune diseases. OBJECTIVES The aim of this study was to decide whether exonic single nucleotide polymorphisms in human leukocyte antigen-G contribute to the risk of developing non-segmental vitiligo in the Korean population. METHODS To evaluate the associations between exonic single nucleotide polymorphisms (rs1630223 [Ala5Ala] and rs12722477 [Leu134Ile]) of human leukocyte antigen-G and vitiligo, 244 patients with vitiligo and 398 healthy controls were recruited. Genotyping was performed using Fluidigm 192.24 Dynamic Array with EP1 (Fluidigm Corp., CA). The SNP type assay (Fluidigm Corp., CA), which employs allele-specifically designed fluorescences (FAM or VIC) primers and a common reverse primer was applied and the data were analysed using the EP1 single nucleotide polymorphisms genotyping analysis software to obtain genotype calls. RESULTS Two exonic single nucleotide polymorphisms (rs1630223 and rs12722477) exhibited significant associations with susceptibility and remained a statistically significant association following Bonferroni correction. These two single nucleotide polymorphisms were located within a block of linkage disequilibrium. Haplotypes G-C and A-A comprising rs1630223 and rs12722477 demonstrated a significant association with non-segmental vitiligo. LIMITATIONS The protein expression level of patients with vitiligo and controls was not studied and a replication study of the genetic association in an independent group was not managed. CONCLUSION Our results suggest that exonic human leukocyte antigen-G polymorphisms (rs1630223 and rs12722477) are associated with the development of non-segmental vitiligo.
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Affiliation(s)
- Su-Kang Kim
- Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung, Seoul, South Korea
| | - Hyo-Eun Kwon
- Department of Dermatology, College of Medicine, Kyung Hee University, Seoul, South Korea
| | - Ki-Heon Jeong
- Department of Dermatology, College of Medicine, Kyung Hee University, Seoul, South Korea
| | - Min Kyung Shin
- Department of Dermatology, College of Medicine, Kyung Hee University, Seoul, South Korea
| | - Mu-Hyoung Lee
- Department of Dermatology, College of Medicine, Kyung Hee University, Seoul, South Korea
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32
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Jasinski-Bergner S, Schmiedel D, Mandelboim O, Seliger B. Role of HLA-G in Viral Infections. Front Immunol 2022; 13:826074. [PMID: 35237271 PMCID: PMC8882596 DOI: 10.3389/fimmu.2022.826074] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/20/2022] [Indexed: 12/18/2022] Open
Abstract
The human leukocyte antigen (HLA)-G is a non-classical HLA class I molecule, which has distinct features to classical HLA-A, -B, -C antigens, such as a low polymorphism, different splice variants, highly restricted, tightly regulated expression and immune modulatory properties. HLA-G expression in tumor cells and virus-infected cells, as well as the release of soluble HLA-G leads to escape from host immune surveillance. Increased knowledge of the link between HLA-G expression, viral infection and disease progression is urgently required, which highlights the possible use of HLA-G as novel diagnostic and prognostic biomarker for viral infections, but also as therapeutic target. Therefore, this review aims to summarize the expression, regulation, function and impact of HLA-G in the context of different viral infections including virus-associated cancers. The characterization of HLA-G-driven immune escape mechanisms involved in the interactions between host cells and viruses might result in the design of novel immunotherapeutic strategies targeting HLA-G and/or its interaction with its receptors on immune effector cells.
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Affiliation(s)
- Simon Jasinski-Bergner
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Dominik Schmiedel
- Department of Good Manufacturing Practice (GMP) Development & Advanced Therapy Medicinal Products (ATMP) Design, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
| | - Ofer Mandelboim
- The Lautenberg Center for General and Tumor Immunology, The BioMedical Research Institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- Department of Good Manufacturing Practice (GMP) Development & Advanced Therapy Medicinal Products (ATMP) Design, Fraunhofer Institute for Cell Therapy and Immunology (IZI), Leipzig, Germany
- *Correspondence: Barbara Seliger,
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33
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Guo Y, Xie Y, Luo Y. The Role of Long Non-Coding RNAs in the Tumor Immune Microenvironment. Front Immunol 2022; 13:851004. [PMID: 35222443 PMCID: PMC8863945 DOI: 10.3389/fimmu.2022.851004] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Tumorigenesis is a complicated process caused by successive genetic and epigenetic alterations. The past decades demonstrated that the immune system affects tumorigenesis, tumor progression, and metastasis. Although increasing immunotherapies are revealed, only a tiny proportion of them are effective. Long non-coding RNAs (lncRNAs) are a class of single-stranded RNA molecules larger than 200 nucleotides and are essential in the molecular network of oncology and immunology. Increasing researches have focused on the connection between lncRNAs and cancer immunotherapy. However, the in-depth mechanisms are still elusive. In this review, we outline the latest studies on the functions of lncRNAs in the tumor immune microenvironment. Via participating in various biological processes such as neutrophil recruitment, macrophage polarization, NK cells cytotoxicity, and T cells functions, lncRNAs regulate tumorigenesis, tumor invasion, epithelial-mesenchymal transition (EMT), and angiogenesis. In addition, we reviewed the current understanding of the relevant strategies for targeting lncRNAs. LncRNAs-based therapeutics may represent promising approaches in serving as prognostic biomarkers or potential therapeutic targets in cancer, providing ideas for future research and clinical application on cancer diagnosis and therapies.
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Affiliation(s)
- Yingli Guo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yajuan Xie
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yao Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
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34
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Li P, Wang N, Zhang Y, Wang C, Du L. HLA-G/sHLA-G and HLA-G-Bearing Extracellular Vesicles in Cancers: Potential Role as Biomarkers. Front Immunol 2021; 12:791535. [PMID: 34868081 PMCID: PMC8636042 DOI: 10.3389/fimmu.2021.791535] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 10/25/2021] [Indexed: 11/15/2022] Open
Abstract
As a non-classic major histocompatibility complex (MHC) class I molecule, human leukocyte antigen G (HLA-G) is expressed in fetal-maternal interface and immunoprivileged site only in healthy condition, and in pathological conditions such as cancer, it can be de novo expressed. It is now widely accepted that HLA-G is a key molecule in the process of immune escape of cancer cells, which is ubiquitously expressed in the tumor environment. This raises the possibility that it may play an adverse role in tumor immunity. The expression level of HLA-G has been demonstrated to be highly correlated with clinical parameters in many tumors, and its potential significance in the diagnosis and prognosis of cancer has been postulated. However, because HLA-G itself has up to seven different subtypes, and for some subtypes, detected antibodies are few or absent, it is hard to evaluate the actual expression of HLA-G in tumors. In the present work, we described (a) the structure and three main forms of HLA-G, (b) summarized the mechanism of HLA-G in the immune escape of tumor cells, (c) discussed the potential role of HLA-G as a tumor marker, and reviewed (d) the methods for detecting and quantifying HLA-G.
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Affiliation(s)
- Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Engineering & Technology Research Center for Tumor Marker Detection , Jinan, China.,Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China
| | - Nan Wang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, China
| | - Yi Zhang
- Department of Respiratory and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Engineering & Technology Research Center for Tumor Marker Detection , Jinan, China.,Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Engineering & Technology Research Center for Tumor Marker Detection , Jinan, China.,Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan, China
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35
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Ayukawa S, Kamoshita N, Nakayama J, Teramoto R, Pishesha N, Ohba K, Sato N, Kozawa K, Abe H, Semba K, Goda N, Fujita Y, Maruyama T. Epithelial cells remove precancerous cells by cell competition via MHC class I-LILRB3 interaction. Nat Immunol 2021; 22:1391-1402. [PMID: 34686865 DOI: 10.1038/s41590-021-01045-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 09/13/2021] [Indexed: 02/04/2023]
Abstract
Epithelial cells have an ability termed 'cell competition', which is an immune surveillance-like function that extrudes precancerous cells from the epithelial layer, leading to apoptosis and clearance. However, it remains unclear how epithelial cells recognize and extrude transformed cells. Here, we discovered that a PirB family protein, leukocyte immunoglobulin-like receptor B3 (LILRB3), which is expressed on non-transformed epithelial cells, recognizes major histocompatibility complex class I (MHC class I) that is highly expressed on transformed cells. MHC class I interaction with LILRB3 expressed on normal epithelial cells triggers an SHP2-ROCK2 pathway that generates a mechanical force to extrude transformed cells. Removal of transformed cells occurs independently of natural killer (NK) cell or CD8+ cytotoxic T cell-mediated activity. This is a new mechanism in that the immunological ligand-receptor system generates a mechanical force in non-immune epithelial cells to extrude precancerous cells in the same epithelial layer.
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Affiliation(s)
- Shiyu Ayukawa
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Nagisa Kamoshita
- Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan
| | - Jun Nakayama
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Ryohei Teramoto
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Novalia Pishesha
- Faculty of Arts and Sciences, Harvard University, Cambridge, MA, USA
| | - Kenji Ohba
- Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Nanami Sato
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Hokkaido, Japan
| | - Kei Kozawa
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Hokkaido, Japan
| | - Hikari Abe
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Kentaro Semba
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Nobuhito Goda
- Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Yasuyuki Fujita
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Hokkaido, Japan.,Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Takeshi Maruyama
- Waseda Institute for Advanced Study, Waseda University, Tokyo, Japan.
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36
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Rao JS, Hosny N, Kumbha R, Naqvi RA, Singh A, Swanson Z, Levy H, Matson AW, Steinhoff M, Forneris N, Walters E, Hering BJ, Burlak C. HLA-G1 + Expression in GGTA1KO Pigs Suppresses Human and Monkey Anti-Pig T, B and NK Cell Responses. Front Immunol 2021; 12:730545. [PMID: 34566993 PMCID: PMC8459615 DOI: 10.3389/fimmu.2021.730545] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/23/2021] [Indexed: 12/04/2022] Open
Abstract
The human leukocyte antigen G1 (HLA-G1), a non-classical class I major histocompatibility complex (MHC-I) protein, is a potent immunomodulatory molecule at the maternal/fetal interface and other environments to regulate the cellular immune response. We created GGTA1-/HLAG1+ pigs to explore their use as organ and cell donors that may extend xenograft survival and function in both preclinical nonhuman primate (NHP) models and future clinical trials. In the present study, HLA-G1 was expressed from the porcine ROSA26 locus by homology directed repair (HDR) mediated knock-in (KI) with simultaneous deletion of α-1-3-galactotransferase gene (GGTA1; GTKO) using the clustered regularly interspersed palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) (CRISPR/Cas9) gene-editing system. GTKO/HLAG1+ pigs showing immune inhibitory functions were generated through somatic cell nuclear transfer (SCNT). The presence of HLA-G1 at the ROSA26 locus and the deletion of GGTA1 were confirmed by next generation sequencing (NGS) and Sanger's sequencing. Fibroblasts from piglets, biopsies from transplantable organs, and islets were positive for HLA-G1 expression by confocal microscopy, flow cytometry, or q-PCR. The expression of cell surface HLA-G1 molecule associated with endogenous β2-microglobulin (β2m) was confirmed by staining genetically engineered cells with fluorescently labeled recombinant ILT2 protein. Fibroblasts obtained from GTKO/HLAG1+ pigs were shown to modulate the immune response by lowering IFN-γ production by T cells and proliferation of CD4+ and CD8+ T cells, B cells and natural killer (NK) cells, as well as by augmenting phosphorylation of Src homology region 2 domain-containing phosphatase-2 (SHP-2), which plays a central role in immune suppression. Islets isolated from GTKO/HLA-G1+ genetically engineered pigs and transplanted into streptozotocin-diabetic nude mice restored normoglycemia, suggesting that the expression of HLA-G1 did not interfere with their ability to reverse diabetes. The findings presented here suggest that the HLA-G1+ transgene can be stably expressed from the ROSA26 locus of non-fetal maternal tissue at the cell surface. By providing an immunomodulatory signal, expression of HLA-G1+ may extend survival of porcine pancreatic islet and organ xenografts.
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Affiliation(s)
- Joseph Sushil Rao
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
- Division of Solid Organ Transplantation, Department of Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Nora Hosny
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
- Medical Biochemistry and Molecular Biology Department, Suez Canal University, Faculty of Medicine, Ismailia, Egypt
| | - Ramesh Kumbha
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Raza Ali Naqvi
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Amar Singh
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Zachary Swanson
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Heather Levy
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Anders W. Matson
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Magie Steinhoff
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Nicole Forneris
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Eric Walters
- Independent Consultant, Centralia, MO, United States
| | - Bernhard J. Hering
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
| | - Christopher Burlak
- Department of Surgery, Schulze Diabetes Institute, University of Minnesota, Minneapolis, MN, United States
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Abstract
Dendritic cells (DCs) are efficient antigen-presenting cells that serve as a link between the innate and adaptive immune systems. These cells are broadly involved in cellular and humoral immune responses by presenting antigens to initiate T cell reactions, cytokine and chemokine secretion, T cell differentiation and expansion, B cell activation and regulation, and the mediation of immune tolerance. The functions of DCs depend on their activation status, which is defined by the stages of maturation, phenotype differentiation, and migration ability, among other factors. IL-6 is a soluble mediator mainly produced by a variety of immune cells, including DCs, that exerts pleiotropic effects on immune and inflammatory responses through interaction with specific receptors expressed on the surface of target cells. Here, we review the role of IL-6, when generated in an inflammatory context or as derived from DCs, in modulating the biologic function and activation status of DCs and emphasize the importance of searching for novel strategies to target the IL-6/IL-6 signaling pathway as a means to diminish the inflammatory activity of DCs in immune response or to prime the immunogenic activity of DCs in immunosuppressive conditions.
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Affiliation(s)
- Yu-Dong Xu
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mi Cheng
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Pan-Pan Shang
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-Qing Yang
- Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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38
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Abstract
Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.
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Affiliation(s)
- Defne Bayik
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
- Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Justin D Lathia
- Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Cleveland, OH, USA.
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39
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Babay W, Boujelbene N, Ben Yahia H, Bortolotti D, Zemni I, Ouzari HI, Chelbi H, Mezlini A, Rizzo R, Zidi I. Prognostic significance of high circulating sHLA-G in ovarian carcinoma. HLA 2021; 98:357-365. [PMID: 34272932 DOI: 10.1111/tan.14374] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 07/14/2021] [Indexed: 12/15/2022]
Abstract
HLA-G is a non-classical major histocompatibility complex class Ib molecule. Its expression has been described in various cancer types, including ovarian cancer. HLA-G molecule has been implicated in immune escape and in progression of ovarian tumor cells. Our goal was to assess if total soluble (s)HLA-G molecules or HLA-G5 and sHLA-G1 isoforms could be considered as circulating ovarian tumor biomarkers, we measured the concentration of these molecules in ovarian carcinoma patients stratified according with their clinicopathological parameters. sHLA-G, sHLA-G1 and HLA-G5 concentrations were dosed in plasma samples by sandwich-ELISA. The sHLA-G dimerization was analyzed after immunoprecipitation and SDS-PAGE migration. Total sHLA-G and sHLA-G1 levels were significantly represented in plasma of ovarian carcinoma patients compared to healthy controls. sHLA-G1 isoform concentration was highly represented in ovarian carcinoma compared to HLA-G5 isoforms. Additionally, high sHLA-G molecules have been found in aged patients, as well as in patients with advanced stages, and those with metastatic lymph nodes and those with distant metastasis. Elsewhere, sHLA-G monomers were highly represented in ovarian carcinoma patients compared to controls. sHLA-G plasmatic protein was highly represented in ovarian carcinoma. In effect, HLA-G might be considered as a new checkpoint molecule that could be used to assess progression and recurrence of the disease, thus placing it as a potential biomarker for advanced and complicated ovarian carcinoma.
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Affiliation(s)
- Wafa Babay
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Nadia Boujelbene
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia.,Department of Pathology, Salah Azaiz Institute, Tunis, Tunisia
| | - Hamza Ben Yahia
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Daria Bortolotti
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - Ines Zemni
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia.,Department of Surgical oncology, Salah Azaiz Institute, Tunis, Tunisia
| | - Hadda-Imene Ouzari
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - Hanene Chelbi
- Laboratory of Medical Parasitology, Biotechnology and Biomolecules, Pasteur Institute of Tunis, Tunis, Tunisia
| | - Amel Mezlini
- Department of Medical Oncology, Salah Azaiz Institute, Tunis, Tunisia
| | - Roberta Rizzo
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - Inès Zidi
- Laboratory Microorganismes and Active Biomolecules, Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis, Tunisia
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40
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Diversity of T Helper and Regulatory T Cells and Their Contribution to the Pathogenesis of Allergic Diseases. Handb Exp Pharmacol 2021; 268:265-296. [PMID: 34247282 DOI: 10.1007/164_2021_486] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
T helper (Th) and regulatory T (Treg) cells represent important effectors of adaptive immunity. They mediate communication between the immune system and tissue sites and thereby coordinate effective defense against environmental threats or maintain tolerance, respectively. Since the discovery of two prototypic T helper cells, Th1 and Th2, additional phenotypic and functional distinct subsets have been described ranging from Th17, Th22, Th9, and T follicular helper cells. The same holds true for regulatory T cells that represent a family with functionally distinct subsets characterized by co-expression of the transcription factors T-bet, Gata3, or RORγt. Here, we summarize the current knowledge on differentiation and function of T helper and regulatory T cell subsets and discuss their lineage stability versus plasticity towards other subsets. In addition, we highlight the direct and indirect contribution of each subset to the pathology of allergies and indicate novel therapies for specific targeting the effector functions of T helper and regulatory T cells.
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41
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Lin A, Yan WH. HLA-G/ILTs Targeted Solid Cancer Immunotherapy: Opportunities and Challenges. Front Immunol 2021; 12:698677. [PMID: 34276691 PMCID: PMC8278316 DOI: 10.3389/fimmu.2021.698677] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/14/2021] [Indexed: 12/04/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have become a promising immunotherapy for cancers. Human leukocyte antigen-G (HLA-G), a neoantigen, its biological functions and clinical relevance have been extensively investigated in malignancies, and early clinical trials with “anti-HLA-G strategy” are being launched for advance solid cancer immunotherapy. The mechanism of HLA-G as a new ICI is that HLA-G can bind immune cell bearing inhibitory receptors, the immunoglobulin-like transcript (ILT)-2 and ILT-4. HLA-G/ILT-2/-4 (HLA-G/ILTs) signaling can drive comprehensive immune suppression, promote tumor growth and disease progression. Though clinical benefits could be expected with application of HLA-G antibodies to blockade the HLA-G/ILTs signaling in solid cancer immunotherapy, major challenges with the diversity of HLA-G isoforms, HLA-G/ILTs binding specificity, intra- and inter-tumor heterogeneity of HLA-G, lack of isoform-specific antibodies and validated assay protocols, which could dramatically affect the clinical efficacy. Clinical benefits of HLA-G-targeted solid cancer immunotherapy may be fluctuated or even premature unless major challenges are addressed.
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Affiliation(s)
- Aifen Lin
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China.,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Linhai, China
| | - Wei-Hua Yan
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Linhai, China.,Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
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42
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Bu X, Zhong J, Li W, Cai S, Gao Y, Ping B. Immunomodulating functions of human leukocyte antigen-G and its role in graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2021; 100:1391-1400. [PMID: 33709198 PMCID: PMC8116272 DOI: 10.1007/s00277-021-04486-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 03/02/2021] [Indexed: 11/28/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic strategy to treat several hematological malignancies and non-hematological malignancies. However, graft-versus-host disease (GVHD) is a frequent and serious transplant-related complication which dramatically restrains the curative effect of allo-HSCT and a significant cause of morbidity and mortality in allogeneic HCT recipients. Effective prevention of GVHD mainly depends on the induction of peripheral immune tolerance. Human leukocyte antigen-G (HLA-G) is a non-classical MHC class I molecule with a strong immunosuppressive function, which plays a prominent role in immune tolerance. HLA-G triggers different reactions depending on the activation state of the immune cells and system. It also exerts a long-term immune tolerance mechanism by inducing regulatory cells. In this present review, we demonstrate the immunomodulatory properties of human leukocyte antigen-G and highlight the role of HLA-G as an immune regulator of GVHD. Furthermore, HLA-G could also serve as a good predictor of GVHD and represent a new therapeutic target for GVHD.
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Affiliation(s)
- Xiaoyin Bu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Jinman Zhong
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Weiru Li
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Shengchun Cai
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China
| | - Ya Gao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
| | - Baohong Ping
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
- Department of Huiqiao, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, China.
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43
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Lekva T, Jacobsen DP, Sugulle M, Moe K, Fjeldstad HES, Dechend R, Staff AC. Circulating HLA-G and its association with cardiovascular markers in pregnancy. J Reprod Immunol 2021; 146:103331. [PMID: 34030048 DOI: 10.1016/j.jri.2021.103331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 05/06/2021] [Accepted: 05/16/2021] [Indexed: 11/29/2022]
Abstract
Human Leukocyte Antigen-G (HLA-G) prevents the activity of immune cells and is decreased in women with preeclampsia. We aimed to investigate the associations between circulating soluble HLA-G (sHLA-G) and 92 cardiovascular disease-related biomarkers from a previously published multiplex study in women with preeclampsia and controls. We found 15 markers significantly associated with circulating sHLA-G in univariate analyses. After multivariable adjusted regression, only proto-oncogene tyrosine-protein kinase Src (SRC) and vascular endothelial growth factor D were significantly associated with sHLA-G. Low SRC, previously observed in the circulation of preeclamptic women, may be regulated by low sHLA-G, and reflect decreased trophoblast differentiation and syncytical formation.
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Affiliation(s)
- Tove Lekva
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Norway.
| | - Daniel P Jacobsen
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway
| | - Meryam Sugulle
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway
| | - Kjartan Moe
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway; Department of Obstetrics and Gynaecology, Bærum Hospital, Vestre Viken Hospital Trust, Norway
| | - Heidi E S Fjeldstad
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Ralf Dechend
- Experimental and Clinical Research Center, A Cooperation of Charité-Universitätsmedizin Berlin and Max-Delbruck Center for Molecular Medicine, Germany; Department of Cardiology and Nephrology, HELIOS-Klinikum, Berlin, Germany
| | - Anne Cathrine Staff
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
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44
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Chen QY, Chen YX, Han QY, Zhang JG, Zhou WJ, Zhang X, Ye YH, Yan WH, Lin A. Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer. Front Immunol 2021; 12:679090. [PMID: 34054869 PMCID: PMC8155601 DOI: 10.3389/fimmu.2021.679090] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 05/04/2021] [Indexed: 12/13/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.
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Affiliation(s)
- Qiong-Yuan Chen
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Yu-Xin Chen
- Alberta Institute, Wenzhou Medical University, Wenzhou, China
| | - Qiu-Yue Han
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Jiang-Gang Zhang
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Wen-Jun Zhou
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Xia Zhang
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China.,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Yao-Han Ye
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Wei-Hua Yan
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China.,Medical Research Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
| | - Aifen Lin
- Biological Resource Center, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China.,Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, China
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45
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Yousefzadeh Y, Soltani-Zangbar MS, Hemmatzadeh M, Shomali N, Mahmoodpoor A, Ahmadian Heris J, Yousefi M. Fetomaternal Immune Tolerance: Crucial Mechanisms of Tolerance for Successful Pregnancy in Humans. Immunol Invest 2021; 51:1108-1125. [PMID: 33830854 DOI: 10.1080/08820139.2021.1909061] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
For many years, the question of how the maternal immune system tolerates the foreign fetus has remained unanswered, and numerous studies have considerably attempted to elucidate underlying mechanisms for fetomaternal tolerance. This review aimed at discussing various significant mechanisms in fetomaternal compatibility. At the fetomaternal interface, in addition to having efficient control against infections, innate and adaptive maternal immune systems selectively prevent fetal rejection. In general, understanding the complex mechanisms of fetomaternal tolerance is critical for immunologic tolerance induction and spontaneous abortion prevention in high-risk populations. Different cells and molecules, such as regulatory T-cells, dendritic cells, decidua cells, IDO, Class I HLA molecules, TGF-β, and IL-10, induce maternal immune tolerance in the fetus in numerous ways. The findings on fetomaternal immune tolerance have remained controversial and require further research.
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Affiliation(s)
- Yousef Yousefzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Committee Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Sadegh Soltani-Zangbar
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Hemmatzadeh
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navid Shomali
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ata Mahmoodpoor
- Department of Anesthesiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Ahmadian Heris
- Department of Allergy and Clinical Immunology, Pediatric Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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46
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Li X, Sheng Z, Sun Y, Wang Y, Xu M, Zhang Z, Li H, Shao L, Zhang Y, Yu J, Ma C, Gao C, Hou M, Ni H, Peng J, Ma J, Feng Q. Human leukocyte antigen-G upregulates immunoglobulin-like transcripts and corrects dysfunction of immune cells in immune thrombocytopenia. Haematologica 2021; 106:770-781. [PMID: 32079695 PMCID: PMC7927897 DOI: 10.3324/haematol.2018.204040] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Indexed: 12/13/2022] Open
Abstract
Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class I antigen with potent immune-inhibitory function. HLA-G benefit patients in allotransplantation and autoimmune diseases by interacting with its receptors, immunoglobulinlike transcripts. Here we observed significantly less HLA-G in plasma from immune thrombocytopenia (ITP) patients positive for anti-platelet autoantibodies compared with autoantibodies-negative patients or healthy controls, while we found that HLA-G is positively correlated with platelet counts in both patients and healthy controls. We also found less membranebound HLA-G and immunoglobulin-like transcripts on CD4+ and CD14+ cells in patients. Recombinant HLA-G upregulated immunoglobulin-like transcript 2 expression on CD4+ and immunoglobulin-like transcript 4 on CD14+ cells. HLA-G upregulated IL-4 and IL-10, and downregulated tumor necrosis factor-a, IL-12 and IL-17 secreted by patient peripheral blood mononuclear cells, suggesting a stimulation of Th2 differentiation and downregulation of Th1 and Th17 immune response. HLA-G-modulated dendritic cells from ITP patients showed decreased expression of CD80 and CD86, and suppressed CD4+ T-cell proliferation compared to unmodulated cells. Moreover, HLA-G-modulated cells from patients induced less platelet apoptosis. HLA-G administration also significantly alleviated thrombocytopenia in a murine model of ITP. In conclusion, our data demonstrated that impaired expression of HLA-G and immunoglobulin-like transcripts is involved in the pathogenesis of ITP; recombinant HLA-G can correct this abnormality via upregulation of immunoglobulin-like transcripts, indicating that HLA-G can be a diagnostic marker and a therapeutic option for ITP.
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Affiliation(s)
- Xin Li
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Zi Sheng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Yuanxin Sun
- Department of Medical Oncology, Shandong Provincial Institute of Cancer Prevention and Treatment, Shandong Cancer Hospital, Shandong University, Jinan, China
| | - Yuanjian Wang
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Miao Xu
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Zhiyue Zhang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Hui Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Linlin Shao
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
| | - Yanqi Zhang
- Department of Medical Oncology, Shandong Provincial Institute of Cancer Prevention and Treatment, Shandong Cancer Hospital, Shandong University, Jinan, China
| | - Jinming Yu
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Chunhong Ma
- Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Chengjiang Gao
- Department of Immunology, Shandong University School of Medicine, Jinan, China
| | - Ming Hou
- Department of Medical Oncology, Shandong Provincial Institute of Cancer Prevention and Treatment, Shandong Cancer Hospital, Shandong University, Jinan, China
| | - Heyu Ni
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada,Toronto Platelet Immunobiology Group, University of Toronto, Toronto, Ontario, Canada,Department of Laboratory Medicine, Keenan Research Center for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada,Canadian Blood Services Center for Innovation, Toronto, Ontario, Canada
| | - Jun Peng
- Department of Medical Oncology, Shandong Provincial Institute of Cancer Prevention and Treatment, Shandong Cancer Hospital, Shandong University, Jinan, China
| | - Ji Ma
- Department of Medical Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China,Department of Medical Oncology, Tianjin Medical University, Tianjin, China
| | - Qi Feng
- Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
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Gao A, Liu X, Lin W, Wang J, Wang S, Si F, Huang L, Zhao Y, Sun Y, Peng G. Tumor-derived ILT4 induces T cell senescence and suppresses tumor immunity. J Immunother Cancer 2021; 9:e001536. [PMID: 33653799 PMCID: PMC7929805 DOI: 10.1136/jitc-2020-001536] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Current immunotherapies including checkpoint blockade therapy have limited success rates in certain types of cancers. Identification of alternative checkpoint molecules for the development of effective strategies for tumor immunotherapy is urgently needed. Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule expressed in both myeloid innate cells and malignant tumor cells. However, the role of tumor-derived ILT4 in regulating cancer biology and tumor immunity remains unclear. METHODS ILT4 expression in tumor cells and patient samples was determined by real-time PCR, flow cytometry, and immunohistochemistry. T cell senescence induced by tumor was evaluated using multiple markers and assays. Moreover, metabolic enzyme and signaling molecule expression and lipid droplets in tumor cells were determined using real-time PCR, western blot and oil red O staining, respectively. Loss-of-function and gain-of-function strategies were used to identify the causative role of ILT4 in tumor-induced T cell senescence. In addition, breast cancer and melanoma mouse tumor models were performed to demonstrate the role of ILT4 as a checkpoint molecule for tumor immunotherapy. RESULTS We reported that ILT4 is highly expressed in human tumor cells and tissues, which is negatively associated with clinical outcomes. Furthermore, tumor-derived ILT4/PIR-B (ILT4 ortholog in mouse) is directly involved in induction of cell senescence in naïve/effector T cells mediated by tumor cells in vitro and in vivo. Mechanistically, ILT4/PIR-B increases fatty acid synthesis and lipid accumulation in tumor cells via activation of MAPK ERK1/2 signaling, resulting in promotion of tumor growth and progression, and induction of effector T cell senescence. In addition, blocking tumor-derived PIR-B can reprogram tumor metabolism, prevent senescence development in tumor-specific T cells, and enhance antitumor immunity in both breast cancer and melanoma mouse models. CONCLUSIONS These studies identify a novel mechanism responsible for ILT4-mediated immune suppression in the tumor microenvironment, and prove a novel concept of ILT4 as a critical checkpoint molecule for tumor immunotherapy.
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MESH Headings
- Animals
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Immunosenescence
- Immunotherapy, Adoptive
- Lymphocytes, Tumor-Infiltrating/immunology
- Lymphocytes, Tumor-Infiltrating/metabolism
- Male
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, SCID
- Neoplasms/immunology
- Neoplasms/metabolism
- Neoplasms/pathology
- Neoplasms/therapy
- Paracrine Communication
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- T-Lymphocytes/transplantation
- Tumor Escape
- Tumor Microenvironment
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Affiliation(s)
- Aiqin Gao
- Department of Oncology, Jinan Central Hospital, affiliated to Shandong University Cheeloo College of Medicine and Shandong First Medical University, Jinan, Shandong, China
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Xia Liu
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Wenli Lin
- Department of Oncology, Jinan Central Hospital, affiliated to Shandong University Cheeloo College of Medicine and Shandong First Medical University, Jinan, Shandong, China
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Jingnan Wang
- Department of Oncology, Jinan Central Hospital, affiliated to Shandong University Cheeloo College of Medicine and Shandong First Medical University, Jinan, Shandong, China
| | - Shuyun Wang
- Department of Oncology, Jinan Central Hospital, affiliated to Shandong University Cheeloo College of Medicine and Shandong First Medical University, Jinan, Shandong, China
| | - Fusheng Si
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Lan Huang
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Yangjing Zhao
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital, affiliated to Shandong University Cheeloo College of Medicine and Shandong First Medical University, Jinan, Shandong, China
| | - Guangyong Peng
- Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, Missouri, USA
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Chen X, Gao A, Zhang F, Yang Z, Wang S, Fang Y, Li J, Wang J, Shi W, Wang L, Zheng Y, Sun Y. ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation. Theranostics 2021; 11:3392-3416. [PMID: 33537094 PMCID: PMC7847666 DOI: 10.7150/thno.52435] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Rationale: Immune checkpoint inhibitors (ICIs) against the PD-1/PD-L1 pathway showed limited success in non-small cell lung cancer (NSCLC) patients, especially in those with activating epidermal growth factor receptor (EGFR) mutations. Elucidation of the mechanisms underlying EGFR-mediated tumor immune escape and the development of effective immune therapeutics are urgently needed. Immunoglobulin-like transcript (ILT) 4, a crucial immunosuppressive molecule initially identified in myeloid cells, is enriched in solid tumor cells and promotes the malignant behavior of NSCLC. However, the upstream regulation of ILT4 overexpression and its function in tumor immunity of NSCLC with EGFR activation remains unclear. Methods: ILT4 expression and EGFR phosphorylation in human NSCLC tissues and cell lines were analyzed using immunohistochemistry (IHC), real-time PCR, Western blotting, immunofluorescence, and flow cytometry. The molecular signaling for EGFR-regulated ILT4 expression was investigated using mRNA microarray and The Cancer Genome Atlas (TCGA) database analyses and then confirmed by Western blotting. The regulation of tumor cell proliferation and apoptosis by ILT4 was examined by CCK8 proliferation and apoptosis assays. The impact of ILT4 and PD-L1 on tumor-associated macrophage (TAM) recruitment and polarization was evaluated using Transwell migration assay, flow cytometry, enzyme linked immunosorbent assay (ELISA) and real-time PCR, while their impact on T cell survival and cytotoxicity was analyzed by CFSE proliferation assay, apoptotic assay, flow cytometry, ELISA and cytolytic assay. Tumor immunotherapy models targeting at paired Ig-like receptor B (PIR-B, an ortholog of ILT4 in mouse)/ILT4 and/or PD-L1 were established in C57BL/6 mice inoculated with stable EGFR- overexpressing Lewis lung carcinoma (LLC) cells and in humanized NSG mice inoculated with EGFR mutant, gefitinib-resistant PC9 (PC9-GR) or EGFR-overexpressing wild type H1299 cells. PIR-B and ILT4 inhibition was implemented by infection of specific knockdown lentivirus and PD-L1 was blocked using human/mouse neutralizing antibodies. The tumor growth model was established in NSG mice injected with PIR-B-downregulated LLC cells to evaluate the effect of PIR-B on tumor proliferation. The frequencies and phenotypes of macrophages and T cells in mouse spleens and blood were detected by flow cytometry while those in tumor tissues were determined by IHC and immunofluorescence. Results: We found that ILT4 expression in tumor cells was positively correlated with EGFR phosphorylation in human NSCLC tissues. Using NSCLC cell lines, we demonstrated that ILT4 was upregulated by both tyrosine kinase mutation-induced and epidermal growth factor (EGF)-dependent EGFR activation and subsequent AKT/ERK1/2 phosphorylation. Overexpressed ILT4 in EGFR-activated tumor cells induced TAM recruitment and M2-like polarization, which impaired T cell function. ILT4 also directly inhibited T cell proliferation, cytotoxicity, and IFN-γ expression and secretion. In EGFR-activated cell lines in vitro and in wild-type EGFR-activated C57BL/6 and humanized NSG immunotherapy models in vivo, either ILT4 (PIR-B) or PD-L1 inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immuno-suppressive TME; the combined inhibition of both molecules showed the most dramatic tumor retraction. Surprisingly, in EGFR mutant, TKI resistant humanized NSG immunotherapy model, ILT4 inhibition alone rather than in combination with a PD-L1 inhibitor suppressed tumor growth and immune evasion. Conclusions: ILT4 was induced by activation of EGFR-AKT and ERK1/2 signaling in NSCLC cells. Overexpressed ILT4 suppressed tumor immunity by recruiting M2-like TAMs and impairing T cell response, while ILT4 inhibition prevented immunosuppression and tumor promotion. Furthermore, ILT4 inhibition enhanced the efficacy of PD-L1 inhibitor in EGFR wild-type but not in EGFR mutant NSCLC. Our study identified novel mechanisms for EGFR-mediated tumor immune escape, and provided promising immunotherapeutic strategies for patients with EGFR-activated NSCLC.
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49
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Kumano S, Okushi Y, Fujimoto K, Adachi H, Furuichi K, Yokoyama H. Role and expression of non-classical human leukocyte antigen-G in renal transplanted allografts. Clin Exp Nephrol 2021; 25:428-438. [PMID: 33398603 DOI: 10.1007/s10157-020-01999-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The non-classical class I molecule human leukocyte antigen-G (HLA-G) has great potential to modulate the immune response. However, the mechanism underlying HLA-G induction remains unknown. Therefore, this study aimed to determine the factors that induce HLA-G expression on proximal tubular epithelial cells (pTECs) in renal transplanted allografts in vivo and in vitro. METHODS This study included 40 adult Japanese patients with renal allografts (35 and five patients with kidneys from living and deceased donors, respectively) who survived for at least 1 year. We evaluated HLA-G1/5 expression using an immunofluorescence method and investigated the induction of HLA-G expression in primary cultured human pTECs by cytokines and immunosuppressants. RESULTS The HLA-G expression was identified in the perinuclear region or on the basement membrane of pTECs of renal biopsy tissue in 12 (30%) of 40 patients at 2-4 weeks and at 1 year following transplantation. A reduction of 30% in the estimated glomerular filtration rate was lower in the HLA-G-positive group than that of the negative group (p = 0.016). Cox proportional hazard models also demonstrated that HLA-G1/5 expression on pTECs was an independent predictor of improved renal allograft function (hazard ratio, 0.189; 95% CI 0.041-0.850, p = 0.030). Interferon-beta was the most powerful inducer of HLA-G expression in vitro, whereas the immunosuppressants everolimus, tacrolimus, cyclosporin, and dexamethasone did not induce any expression. CONCLUSION Unlike immunosuppressants, acquired HLA-G expression might confer long-term renal preservation effects in renal transplanted allografts.
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Affiliation(s)
- Sho Kumano
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
| | - Yuki Okushi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Keiji Fujimoto
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hiroki Adachi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Kengo Furuichi
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan
| | - Hitoshi Yokoyama
- Department of Nephrology, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Ishikawa, 920-0293, Japan.
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50
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Zhang X, Lin A, Han QY, Zhang JG, Chen QY, Ye YH, Zhou WJ, Xu HH, Gan J, Yan WH. Intratumor Heterogeneity of HLA-G Expression in Cancer Lesions. Front Immunol 2020; 11:565759. [PMID: 33329527 PMCID: PMC7717930 DOI: 10.3389/fimmu.2020.565759] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 10/27/2020] [Indexed: 01/05/2023] Open
Abstract
Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.
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Affiliation(s)
- Xia Zhang
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Aifen Lin
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Qiu-Yue Han
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Jian-Gang Zhang
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Qiong-Yuan Chen
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Yao-Han Ye
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Wen-Jun Zhou
- Biological Resource Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Hui-Hui Xu
- Medical Research Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Jun Gan
- Medical Research Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
| | - Wei-Hua Yan
- Medical Research Center, TaiZhou Hospital of Zhejiang Province, Taizhou Enze Medical Center (Group), LinHai, China
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