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Tan SN, Hao J, Ge J, Yang Y, Liu L, Huang J, Lin M, Zhao X, Wang G, Yang Z, Ni L, Dong C. Regulatory T cells converted from Th1 cells in tumors suppress cancer immunity via CD39. J Exp Med 2025; 222:e20240445. [PMID: 39907686 DOI: 10.1084/jem.20240445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 10/17/2024] [Accepted: 01/10/2025] [Indexed: 02/06/2025] Open
Abstract
Regulatory T (Treg) cells are known to impede antitumor immunity, yet the regulatory mechanisms and functional roles of these cells remain poorly understood. In this study, through the characterization of multiple cancer models, we identified a substantial presence of peripherally induced Treg cells in the tumor microenvironment (TME). Depletion of these cells triggered antitumor responses and provided potent therapeutic effects by increasing functional CD8+ T cells. Fate-mapping and transfer experiments revealed that IFN-γ-expressing T helper (Th) 1 cells differentiated into Treg cells in response to TGF-β signaling in tumors. Pseudotime trajectory analysis further revealed the terminal differentiation of Th1-like Treg cells from Th1 cells in the TME. Tumor-resident Treg cells highly expressed T-bet, which was essential for their functions in the TME. Additionally, CD39 was highly expressed by T-bet+ Treg cells in both mouse and human tumors, and was necessary for Treg cell-mediated suppression of CD8+ T cell responses. Our study elucidated the developmental pathway of intratumoral Treg cells and highlighted novel strategies for targeting them in cancer patients.
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Affiliation(s)
- Sang-Nee Tan
- School of Medicine, Westlake University , Hangzhou, China
- Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China
| | - Jing Hao
- Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China
- Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital , Shanghai, China
| | - Jing Ge
- Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital , Shanghai, China
| | - Yazheng Yang
- Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China
| | - Liguo Liu
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Jia Huang
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Meng Lin
- School of Medicine, Westlake University , Hangzhou, China
| | - Xiaohong Zhao
- Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China
| | - Genyu Wang
- School of Pharmaceutical Sciences, Shanghai Jiao Tong University , Shanghai, China
| | - Zhiying Yang
- Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, China
| | - Ling Ni
- Institute for Immunology and School of Medicine, Tsinghua University , Beijing, China
| | - Chen Dong
- School of Medicine, Westlake University , Hangzhou, China
- Shanghai Immune Therapy Institute, Shanghai Jiao Tong University School of Medicine-affiliated Renji Hospital , Shanghai, China
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Zhao F, Zhang K, Ma L, Huang Y. Identification of epithelial-related artificial neural network prognostic models for the prediction of bladder cancer prognosis through comprehensive analysis of single-cell and bulk RNA sequencing. Heliyon 2024; 10:e34632. [PMID: 39157397 PMCID: PMC11328080 DOI: 10.1016/j.heliyon.2024.e34632] [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: 05/20/2024] [Revised: 07/03/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
Background Bladder cancer (BLCA) presents as a heterogeneous epithelial malignancy. Progress in the early detection and effective treatment of BLCA relies heavily on the identification of novel biomarkers. Therefore, the primary goal of this study is to pinpoint potential biomarkers for BLCA through the fusion of single-cell RNA sequencing and RNA sequencing assessments. Furthermore, the aim is to establish practical clinical prognostic models that can facilitate accurate categorization and individualized therapy for patients. Methods In this research, training sets were acquired from the TCGA database, whereas validation sets (GSE32894) and single-cell datasets (GSE135337) were extracted from the GEO database. Single-cell analysis was utilized to obtain characteristic subpopulations along with their associated marker genes. Subsequently, a novel BLCA subtype was identified within TCGA-BLCA. Furthermore, an artificial neural network prognostic model was constructed within the TCGA-BLCA cohort and subsequently verified utilizing a validation set. Two machine learning algorithms were employed to screen hub genes. QRT-qPCR was performed to detect the gene expression levels utilized in the construction of prognostic models across various cell lines. Additionally, the cMAP database and molecular docking were utilized for searching small molecule drugs. Results The results of single-cell analysis revealed the presence of epithelial cells in multiple subpopulations, with 1579 marker genes selected for subsequent investigations. Subsequently, four epithelial cell subtypes were identified within the TCGA-BLCA cohort. Notably, cluster A exhibited a significant survival advantage. Concurrently, an artificial neural network prognostic model comprising 17 feature genes was constructed, accurately stratifying patient risk. Patients categorized in the low-risk group demonstrated a considerable survival advantage. The ROC analysis suggested that the model has strong prognostic ability. Furthermore, the findings of the validation group align consistently with those from the training group. Two types of machine learning algorithms screened NFIC as hub genes. Forskolin, a small molecule drug that binds to NFIC, was identified by employing a cMAP database and molecular docking. Conclusion The analysis results supplement the research on the role of epithelial cells in BLCA. An artificial neural network prognostic model containing 17 characteristic genes demonstrates the capability to accurately stratify patient risk, thereby potentially improving clinical decision-making and optimizing personalized therapeutic approaches.
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Affiliation(s)
- Fan Zhao
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Kun Zhang
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Limin Ma
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China
| | - Yeqing Huang
- Department of Urology, Affiliated Hospital of Nantong University, Nantong, 226001, China
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Chen Y, Fan W, Zhao Y, Liu M, Hu L, Zhang W. Progress in the Regulation of Immune Cells in the Tumor Microenvironment by Bioactive Compounds of Traditional Chinese Medicine. Molecules 2024; 29:2374. [PMID: 38792234 PMCID: PMC11124165 DOI: 10.3390/molecules29102374] [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: 04/10/2024] [Revised: 05/04/2024] [Accepted: 05/15/2024] [Indexed: 05/26/2024] Open
Abstract
The tumor microenvironment (TME) can aid tumor cells in evading surveillance and clearance by immune cells, creating an internal environment conducive to tumor cell growth. Consequently, there is a growing focus on researching anti-tumor immunity through the regulation of immune cells within the TME. Various bioactive compounds in traditional Chinese medicine (TCM) are known to alter the immune balance by modulating the activity of immune cells in the TME. In turn, this enhances the body's immune response, thus promoting the effective elimination of tumor cells. This study aims to consolidate recent findings on the regulatory effects of bioactive compounds from TCM on immune cells within the TME. The bioactive compounds of TCM regulate the TME by modulating macrophages, dendritic cells, natural killer cells and T lymphocytes and their immune checkpoints. TCM has a long history of having been used in clinical practice in China. Chinese medicine contains various chemical constituents, including alkaloids, polysaccharides, saponins and flavonoids. These components activate various immune cells, thereby improving systemic functions and maintaining overall health. In this review, recent progress in relation to bioactive compounds derived from TCM will be covered, including TCM alkaloids, polysaccharides, saponins and flavonoids. This study provides a basis for further in-depth research and development in the field of anti-tumor immunomodulation using bioactive compounds from TCM.
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Affiliation(s)
- Yuqian Chen
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
- Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang 261053, China
| | - Wenshuang Fan
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
| | - Yanyan Zhao
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
- Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang 261053, China
| | - Meijun Liu
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
- Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang 261053, China
| | - Linlin Hu
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
- Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang 261053, China
| | - Weifen Zhang
- School of Pharmacy, Shandong Second Medical University, Weifang 261053, China; (Y.C.); (W.F.); (Y.Z.); (M.L.)
- Shandong Engineering Research Center for Smart Materials and Regenerative Medicine, Weifang 261053, China
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Bergman PJ. Cancer Immunotherapy. Vet Clin North Am Small Anim Pract 2024; 54:441-468. [PMID: 38158304 DOI: 10.1016/j.cvsm.2023.12.002] [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] [Indexed: 01/03/2024]
Abstract
The enhanced understanding of immunology experienced over the last 5 decades afforded through the tools of molecular biology has recently translated into cancer immunotherapy becoming one of the most exciting and rapidly expanding fields. Human cancer immunotherapy is now recognized as one of the pillars of treatment alongside surgery, radiation, and chemotherapy. The field of veterinary cancer immunotherapy has also rapidly advanced in the last decade with a handful of commercially available products and a plethora of investigational cancer immunotherapies, which will hopefully expand our veterinary oncology treatment toolkit over time.
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Affiliation(s)
- Philip J Bergman
- Clinical Studies, VCA; Katonah Bedford Veterinary Center, Bedford Hills, NY, USA; Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Nagai H, Mukozu T, Matsui T, Mohri K, Nagumo H, Yoshimine N, Kobayashi K, Ogino Y, Daido Y, Wakui N, Momiyama K, Matsuda T, Igarashi Y, Higai K. Remaining Issues Related to Serum Cytokines in Patients with Unresectable Hepatocellular Carcinoma Treated by Atezolizumab plus Bevacizumab Combination Treatment. Oncology 2024; 102:828-840. [PMID: 38402871 DOI: 10.1159/000537965] [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: 01/06/2024] [Accepted: 02/15/2024] [Indexed: 02/27/2024]
Abstract
INTRODUCTION Atezolizumab plus bevacizumab (AteBev) combination treatment is widely used as first-line systemic therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to clarify therapeutic issues regarding serum cytokines and the immune reaction in patients with uHCC treated with AteBev. METHODS We analyzed preserved serum from a previous prospective study on adult Japanese patients with chronic liver disease and uHCC who received AteBev treatment at our hospital. In that study, AteBev was administered intravenously every 3 weeks, and blood samples were collected before and after 3 weeks' treatment. Dynamic computed tomography was performed after 6 weeks of treatment to assess response. RESULTS In the prospective study, 21 of the 59 patients showed partial response (PR) and 19 patients showed stable disease, but 19 patients showed progressive disease (PD). We found that serum levels of tumor necrosis factor-alpha, interleukin (IL)-6, and soluble IL-2 receptor (IL-2R) increased significantly in the PR group, but only soluble IL-2R increased significantly in the PD group. Regulatory T cells decreased significantly in the PD group, but there was no significant change in Th1 or Th2 cells from before to after treatment in any group. As regards soluble MHC-class I, pre-treatment levels were significantly lower in the PD group than in the PR group, and serum levels increased significantly with treatment in the PD group. CONCLUSION These findings reveal a need to further improve T-cell priming and to further make T cells recognize tumor antigens in uHCC.
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Affiliation(s)
- Hidenari Nagai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takanori Mukozu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Teppei Matsui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kunihide Mohri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Hideki Nagumo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Naoyuki Yoshimine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kojiro Kobayashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yu Ogino
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yasuko Daido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Noritaka Wakui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koichi Momiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Takahisa Matsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine (Omori), School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Koji Higai
- Department of Medical Biochemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba, Japan
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Taniura T, Ishitobi K, Hidaka M, Harada M. Modulatory effects of supplementation of Lentinula edodes mycelia extract and l-arginine on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice. Microbiol Immunol 2024; 68:15-22. [PMID: 37964433 DOI: 10.1111/1348-0421.13101] [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: 10/19/2023] [Accepted: 11/02/2023] [Indexed: 11/16/2023]
Abstract
Some chemotherapeutic drugs can induce cancer cell death and enhance antitumor T-cell immunity in cancer-bearing hosts. Immunomodulatory reagents could augment such chemotherapy-induced effects. We previously reported that oral digestion of Lentinula edodes mycelia (L.E.M.) extract or l-arginine supplementation can augment antitumor T-cell responses in cancer-bearing mice. In this study, the effects of L.E.M. extract with or without l-arginine on the therapeutic efficacy of immunogenic chemotherapy by 5-fluorouracil (5-FU)/oxaliplatin (L-OHP) and/or cyclophosphamide (CP) are examined using two mouse colon cancer models. In MC38 and CT26 cancer models, therapy with 5-FU/L-OHP/CP significantly suppressed tumor growth, and supplementation with L.E.M. extract halved the tumor volumes. However, the modulatory effect of L.E.M. extract was not significant. In the CT26 cancer model, supplementation with L.E.M. extract and l-arginine had no clear effect on tumor growth. In contrast, their addition to chemotherapy halved the tumor volumes, although the effect was not significant. There was no difference in the cytotoxicity of tumor-specific cytotoxic T cells generated from CT26-cured mice treated by chemotherapy alone versus chemotherapy combined with L.E.M. extract/ l-arginine. These results indicate that the antitumor effects of immunogenic chemotherapy were too strong to ascertain the effects of supplementation of L.E.M. extract and l-arginine, but these reagents nonetheless have immunomodulatory effects on the therapeutic efficacy of immunogenic chemotherapy in colon cancer-bearing mice.
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Affiliation(s)
- Takahito Taniura
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Kazunari Ishitobi
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Masaaki Hidaka
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, Shimane, Japan
| | - Mamoru Harada
- Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan
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Bretscher P. What Determines the Class of Immunity an Antigen Induces? A Foundational Question Whose Rational Consideration Has Been Undermined by the Information Overload. BIOLOGY 2023; 12:1253. [PMID: 37759652 PMCID: PMC10525557 DOI: 10.3390/biology12091253] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/29/2023]
Abstract
Activated CD4 T helper cells are required to activate B cells to produce antibody and CD8 T cells to generate cytotoxic T lymphocytes. In the absence of such help, antigens inactivate B cells and CD8 T cells. Thus, the activation or inactivation of CD4 T cells determines whether immune responses are generated, or potentially ablated. Most consider that the activation of CD4 T cells requires an antigen-dependent signal, signal 1, as well as a critical costimulatory signal, initiated when a pattern recognition receptor (PRR) engages with a danger- or pathogen-associated molecular pattern (DAMP or PAMP). Most also envisage that the nature of the DAMP/PAMP signal determines the Th subset predominantly generated and so the class of immunity predominantly induced. I argue that this framework is implausible as it is incompatible with diverse observations of the variables of immunization affecting the class of immunity induced. An alternative framework, the threshold hypothesis, posits that different levels of antigen mediated CD4 T cell interactions lead to the generation of different Th subsets and so different classes of immunity, that it is compatible with these observations. This alternative supports a rational approach to preventing and treating diverse clinical conditions associated with infectious disease and, more speculatively, with cancer.
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Affiliation(s)
- Peter Bretscher
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
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Wang J, Zhao X, Wan YY. Intricacies of TGF-β signaling in Treg and Th17 cell biology. Cell Mol Immunol 2023; 20:1002-1022. [PMID: 37217798 PMCID: PMC10468540 DOI: 10.1038/s41423-023-01036-7] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Balanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
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Affiliation(s)
- Junying Wang
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Xingqi Zhao
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yisong Y Wan
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
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Tibbs E, Kandy RRK, Jiao D, Wu L, Cao X. Murine regulatory T cells utilize granzyme B to promote tumor metastasis. Cancer Immunol Immunother 2023; 72:2927-2937. [PMID: 36826509 PMCID: PMC10690887 DOI: 10.1007/s00262-023-03410-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: 10/02/2022] [Accepted: 02/12/2023] [Indexed: 02/25/2023]
Abstract
Regulatory T cells (Tregs) possess a wide range of mechanisms for immune suppression. Among them, Granzyme B (GzmB) and perforin expressed by Tregs were shown to inhibit tumor clearance in previous reports, which contradicted the canonical roles of these cytotoxic molecules expressed by cytotoxic T cells and NK cells in antitumor immune responses. Given the ability of the tumor to manipulate the microenvironment, Treg-derived GzmB function may represent an important approach to aid in tumor growth as well as facilitating tumor metastasis. In this study, we utilized Treg-specific GzmB knockout (Foxp3creGzmBfl/fl) mice to test whether Treg-derived GzmB can aid in tumor progression and metastasis. Using an IL-2 complex to activate GzmB expression in the non-immunogenic B16-F10 tumor model, we provide evidence to show that GzmB produced by Tregs is important for spontaneous metastasis to the lungs. In addition, we depleted CD8 + T cells to selectively measure the impact of Treg-derived GzmB in an experimental lung metastasis model by intravenous injection of B16-F10 tumor cells; our results demonstrate that Treg-derived GzmB plays an important role in increasing the metastatic burden to the lungs.
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Affiliation(s)
- Ellis Tibbs
- Department of Microbiology and Immunology, University of Maryland Baltimore, School of Medicine, Baltimore, MD, 21201, USA
| | - Rakhee Rathnam Kalari Kandy
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, USA
| | - Delong Jiao
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, USA
| | - Long Wu
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, USA
| | - Xuefang Cao
- Department of Microbiology and Immunology, University of Maryland Baltimore, School of Medicine, Baltimore, MD, 21201, USA.
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore, Baltimore, USA.
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Caruso B, Moran AE. Thymic expression of immune checkpoint molecules and their implication for response to immunotherapies. Trends Cancer 2023:S2405-8033(23)00063-8. [PMID: 37173189 DOI: 10.1016/j.trecan.2023.04.007] [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: 01/20/2023] [Revised: 04/07/2023] [Accepted: 04/14/2023] [Indexed: 05/15/2023]
Abstract
The thymus is responsible for generating a diverse T cell repertoire that is tolerant to self, but capable of responding to various immunologic insults, including cancer. Checkpoint blockade has changed the face of cancer treatment by targeting inhibitory molecules, which are known to regulate peripheral T cell responses. However, these inhibitory molecules and their ligands are expressed during T cell development in the thymus. In this review, we describe the underappreciated role of checkpoint molecule expression during the formation of the T cell repertoire and detail the importance of inhibitory molecules in regulating T cell lineage commitment. Understanding how these molecules function in the thymus may inform therapeutic strategies for better patient outcomes.
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Affiliation(s)
- Breanna Caruso
- Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA
| | - Amy E Moran
- Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
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Iglesias-Escudero M, Arias-González N, Martínez-Cáceres E. Regulatory cells and the effect of cancer immunotherapy. Mol Cancer 2023; 22:26. [PMID: 36739406 PMCID: PMC9898962 DOI: 10.1186/s12943-023-01714-0] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 01/02/2023] [Indexed: 02/06/2023] Open
Abstract
Several mechanisms and cell types are involved in the regulation of the immune response. These include mostly regulatory T cells (Tregs), regulatory macrophages (Mregs), myeloid suppressor cells (MDSCs) and other regulatory cell types such as tolerogenic dendritic cells (tolDCs), regulatory B cells (Bregs), and mesenchymal stem cells (MSCs). These regulatory cells, known for their ability to suppress immune responses, can also suppress the anti-tumor immune response. The infiltration of many regulatory cells into tumor tissues is therefore associated with a poor prognosis. There is growing evidence that elimination of Tregs enhances anti-tumor immune responses. However, the systemic depletion of Treg cells can simultaneously cause deleterious autoimmunity. Furthermore, since regulatory cells are characterized by their high level of expression of immune checkpoints, it is also expected that immune checkpoint inhibitors perform part of their function by blocking these molecules and enhancing the immune response. This indicates that immunotherapy does not only act by activating specific effector T cells but can also directly or indirectly attenuate the suppressive activity of regulatory cells in tumor tissues. This review aims to draw together our current knowledge about the effect of immunotherapy on the various types of regulatory cells, and how these effects may be beneficial in the response to immunotherapy.
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Affiliation(s)
- María Iglesias-Escudero
- Immunology Division, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain. .,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
| | - Noelia Arias-González
- grid.411438.b0000 0004 1767 6330Immunology Division, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain
| | - Eva Martínez-Cáceres
- Immunology Division, LCMN, Germans Trias i Pujol University Hospital and Research Institute, Campus Can Ruti, Badalona, Spain. .,Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
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Parisi F, Millanta F, Nicastro M, Vannozzi I, Poli A. Confirmation of the Prognostic Value of Foxp3+ Cells in Canine Mammary Tumors. Animals (Basel) 2023; 13:ani13030505. [PMID: 36766393 PMCID: PMC9913641 DOI: 10.3390/ani13030505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/23/2023] [Accepted: 01/29/2023] [Indexed: 02/04/2023] Open
Abstract
Foxp3+ cell counts were evaluated by immunohistochemistry in 59 canine mammary tumors, 20 adenomas, and 39 carcinomas in three different compartments: intratumoral, within the adjacent stroma, and in the distant stroma. Foxp3+ lymphocyte counts were compared with histotype, grading, presence of lymphatic invasion, immunohistochemical expression of estrogen and progesterone receptors, expression of c-erbB-2, and the overall survival (OS). Our findings confirmed that Foxp3+ cells were significantly higher in canine mammary carcinomas compared to adenomas. A significantly higher number of Foxp3+ cells were detected in grade III carcinomas compared to grade II carcinomas, as well as in tumors with lymphatic invasion and loss of ER-expression. Finally, a high number of Foxp3+ cells was associated with poor prognosis. In conclusion, our findings highlighted the association of Foxp3+ lymphocytes with negative clinicopathological features and shorter overall survival (OS), thus confirming the role of Tregs as a negative prognostic marker in canine mammary carcinomas.
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Takaku S, Shimizu M, Morita R. CD8 + T Cell-Mediated Therapeutic Antitumor Effect of an Herbal Mixture Containing Ganoderma lucidum. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2023; 2023:9630816. [PMID: 37152373 PMCID: PMC10162866 DOI: 10.1155/2023/9630816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/09/2023] [Accepted: 03/23/2023] [Indexed: 05/09/2023]
Abstract
Although Kampo-a traditional Japanese herbal medicine-contributes in the control of tumor growth in vivo in experimental animals, most of the antitumor effects are prophylactic and not therapeutic. In this study, we determined whether oral administration of an herbal mixture containing Ganoderma lucidum (WTMCGEP; Wisteria floribunda, Trapae fructus, Myristica fragrans, Coicis semen, Ganoderma lucidum, Elfvingia applanata, and Punica granatum), anecdotally used in Japan for the palliative care of patients with cancer, exhibits a therapeutic effect on tumor growth in vivo in a hypodermic murine CT26 colorectal tumor model. An in vitro tumor assay revealed that WTMCGEP extract has some direct influence over suppression of tumor growth. In wild-type BALB/c mice, WTMCGEP did not show any antitumor effect in vivo. However, in BALB-CD1d-/- mice with partly mitigated immunosuppression by reason of them being devoid of both antitumoral type I and immunosuppressive type II natural killer T (NKT) cells, WTMCGEP therapeutically suppressed tumor growth. CD8+ T cell depletion significantly accelerated tumor growth in WTMCGEP mice; therefore, its antitumor activity was primarily in a CD8+ T cell-dependent manner. Regarding immunosuppressive cells in tumor-bearing CD1d-/- mice, WTMCGEP did not influence the abundance of tumor-infiltrating CD4+ and Forkhead box protein 3+ regulatory T cells. However, it reduced both intratumoral and splenic Ly6G+ Ly6Clo polymorphonuclear myeloid-derived suppressor cells, which were most likely involved in tumor growth inhibition related to higher frequency of intratumoral CD107a+ CD8+ T cells in these mice. Overall, these data illustrate that the deficiency of NKT cells urges WTMCGEP to exert a therapeutic antitumor effect mainly through CD8+ T cells. Our efforts are the first to scientifically demonstrate the WTMCGEP's contribution to tumor immunity.
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Affiliation(s)
- Shun Takaku
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
- Center for Medical Education, Nippon Medical School, Tokyo 113-8602, Japan
| | - Masumi Shimizu
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Rimpei Morita
- Department of Microbiology and Immunology, Nippon Medical School, Tokyo 113-8602, Japan
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CD3 high and FoxP3 - tumor-infiltrating lymphocytes in the invasive margin as a favorable prognostic marker in patients with invasive urothelial carcinoma of the bladder. Anticancer Drugs 2022:00001813-990000000-00139. [PMID: 36563023 DOI: 10.1097/cad.0000000000001468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Tumor-infiltrating lymphocytes (TILs) have been extensively explored as prognostic biomarkers and cellular immunotherapy methods in cancer patients. However, the prognostic significance of TILs in bladder cancer remains unresolved. We evaluated the prognostic effect of TILs in bladder cancer patients. Sixty-four bladder cancer patients who underwent surgical resection between 2018 and 2020 in Zhejiang Provincial People's Hospital were analyzed in this study. Immunohistochemistry was used to evaluate CD3, CD4, CD8, and FoxP3 expression on TILs in the invasive margin of tumor tissue, and the presence of TIL subsets was correlated with the disease-free survival (DFS) of bladder cancer patients. The relationship between clinical-pathological features and DFS were analyzed. A high level of CD3 + TILs (CD3 high TILs) ( P = 0.027) or negative expression of FoxP3 TILs (FoxP3 - TILs) ( P = 0.016) was significantly related to better DFS in bladder cancer patients. Those with CD3 high FoxP3 - TILs had the best prognosis compared to those with CD3 high FoxP3 + TILs or CD3 low FoxP3 - TILs ( P = 0.0035). Advanced age [HR 4.57, (1.86-11.25); P = 0.001], CD3 low TILs [HR 0.21, (0.06-0.71); P = 0.012], CD8 low TILs [HR 0.34, (0.12-0.94); P = 0.039], and FoxP3 + TILs [HR 10.11 (1.96-52.27); P = 0.006] in the invasive margin were associated with a worse prognosis (DFS) by multivariate analysis. In conclusion, we demonstrated that CD3 high , FoxP3 - , and CD3 high FoxP3 - TILs in the invasive margin were significantly associated with better DFS. CD8 high and CD4 high TILs in the invasive margin tended to predict better DFS in bladder cancer. Patients with CD4 high CD8 high TILs in the invasive margin were likely to have a better prognosis.
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15
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Fan X, Xie F, Zhang L, Tong C, Zhang Z. Identification of immune-related ferroptosis prognostic marker and in-depth bioinformatics exploration of multi-omics mechanisms in thyroid cancer. Front Mol Biosci 2022; 9:961450. [PMID: 36060256 PMCID: PMC9428456 DOI: 10.3389/fmolb.2022.961450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Accepted: 07/18/2022] [Indexed: 11/26/2022] Open
Abstract
Background: Factors such as variations in thyroid carcinoma (THCA) gene characteristics could influence the clinical outcome. Ferroptosis and immunity have been verified to play an essential role in various cancers, and could affect the cancer patients’ prognosis. However, their relationship to the progression and prognosis of many types of THCA remains unclear. Methods: First, we extracted prognosis-related immune-related genes and ferroptosis-related genes from 2 databases for co-expression analysis to obtain prognosis-related differentially expressed immune-related ferroptosis genes (PR-DE-IRFeGs), and screened BID and CDKN2A for building a prognostic model. Subsequently, multiple validation methods were used to test the model’s performance and compare its performance with other 4 external models. Then, we explored the mechanism of immunity and ferroptosis in the occurrence, development and prognosis of THCA from the perspectives of anti-tumor immunity, CDKN2A-related competitive endogenous RNA regulatory, copy number variations and high frequency gene mutation. Finally, we evaluated this model’s clinical practice value. Results: BID and CDKN2A were identified as prognostic risk and protective factors, respectively. External data and qRT-PCR experiment also validated their differential expression. The model’s excellent performance has been repeatedly verified and outperformed other models. Risk scores were significantly associated with most immune cells/functions. Risk score/2 PR-DE-IRFeGs expression was strongly associated with BRAF/NRAS/HRAS mutation. Single copy number deletion of CDKN2A is associated with upregulation of CDKN2A expression and worse prognosis. The predicted regulatory network consisting of CYTOR, hsa-miRNA-873-5p and CDKN2A was shown to significantly affect prognosis. The model and corresponding nomogram have been shown to have excellent clinical practice value. Conclusion: The model can effectively predict the THCA patients’ prognosis and guide clinical treatment. Ferroptosis and immunity may be involved in the THCA’s progression through antitumor immunity and BRAF/NRAS/HRAS mutation. CYTOR-hsa-miRNA-873-5p-CDKN2A regulatory networks and single copy number deletion of CDKN2A may also affect THCA′ progression and prognosis.
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Affiliation(s)
- Xin Fan
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fei Xie
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lingling Zhang
- School of Stomatology, Nanchang University, Nanchang, China
| | - Chang Tong
- Pediatric Medical School, Nanchang University, Nanchang, China
| | - Zhiyuan Zhang
- Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Zhiyuan Zhang,
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16
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Japanese Kampo Medicine Juzentaihoto Improves Antiviral Cellular Immunity in Tumour-Bearing Hosts. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:6122955. [PMID: 35996405 PMCID: PMC9392631 DOI: 10.1155/2022/6122955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 06/05/2022] [Accepted: 06/07/2022] [Indexed: 12/05/2022]
Abstract
Global and antigen-independent immunosuppression by growing tumours can cause life-threating damage when concurrent with an infection in tumour-bearing hosts. In the present study, we investigated whether the oral administration of the Japanese traditional herbal (Kampo) medicine, juzentaihoto (JTT), plays a role in the improvement of antiviral cellular immunity in tumour-bearing hosts. Female BALB/c mice subcutaneously injected with murine colorectal cancer CT26 cells fed a control or JTT diet were inoculated with recombinant vaccinia virus expressing human immunodeficiency virus-1 glycoprotein 160 (vSC25). At 7 days postinfection, anti-vSC25 cellular immunity was evaluated by measuring the abundance of splenic virus-specific CD8+ T cells. JTT had no impact on CT26 tumour growth in vivo. Surprisingly, JTT augmented anti-vSC25 cellular immunity in CT26-bearing mice. Depletion of either CD25+ regulatory T (Treg) cells or myeloid-derived suppressor cells (MDSCs) also enhanced anti-vSC25 cellular immunity in tumour-bearing mice but had no therapeutic benefit against tumour growth. However, JTT had no impact on the abundance of these immunosuppressive cells. Overall, our data indicates that JTT contributes to the improvement of anti-vSC25 cellular immunity in tumour-bearing hosts possibly via a mechanism independent of CD25+ Treg cells and MDSCs, suggesting that this Kampo medicine can act as a promising antiviral adjuvant in an immunosuppressive state caused by tumours.
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Wang YT, Kuo LT, Weng HH, Hsu CM, Tsai MS, Chang GH, Lee YC, Huang EI, Tsai YT. Systemic Immun e–Inflammation Index as a Predictor for Head and Neck Cancer Prognosis: A Meta-Analysis. Front Oncol 2022; 12:899518. [PMID: 35814369 PMCID: PMC9263088 DOI: 10.3389/fonc.2022.899518] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
Background Studies have reported inconsistent results regarding the prognostic value of the systemic immune–inflammation index (SII) in head and neck cancer (HNC). Thus, the present meta-analysis assessed the literature on the prognostic value of SII in those with HNC. Methods The Cochrane Library, EMBASE, and PubMed databases were searched, and study methodological quality was assessed using the Newcastle–Ottawa quality assessment scale. To determine the association of the SII with survival outcomes, pooled hazard ratios (HRs) as well as the associated 95% confidence intervals (CIs) were used. To assess the associations of the SII with clinicopathological features, the odds ratios (ORs) and corresponding 95% CIs were considered. Begg’s funnel plot and Egger’s linear regression test were used to assess publication bias. Results A total of 12 studies that together enrolled 4369 patients with HNC were analyzed. In the pooled results, a high pretreatment SII was correlated with poorer overall survival (HR = 2.09, 95% CI = 1.62–2.70, p < 0.001), disease-free survival (HR = 2.79, 95% CI = 1.99−3.89, p < 0.001), and progression-free survival (HR = 1.80, 95% CI = 1.30−2.48, p < 0.001). A stratified analysis indicated that SII for overall survival was applicable regardless of tumor site, treatment modality, overall stage, sample size, SII cutoff, and method for determining the SII cutoff. Furthermore, a high SII was correlated with a more advanced T classification (OR = 1.14, 95% CI = 1.09–1.18, p < 0.001) and nodal metastasis (OR = 1.55, 95% CI = 1.18–2.05, p = 0.002) in patients with HNC. Conclusions An elevated pretreatment SII predicts more advanced tumor and nodal status and poorer survival outcomes in cases of HNC. Because the measurement of SII is convenient and its use is cost-effective, we suggest that it can be applied by clinicians in the management of HNC.
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Affiliation(s)
- Yun-Ting Wang
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Liang-Tseng Kuo
- Division of Sports Medicine, Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Hsu-Huei Weng
- Department of Radiology, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Cheng-Ming Hsu
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Ming-Shao Tsai
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Geng-He Chang
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yi-Chan Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Ethan I. Huang
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yao-Te Tsai
- Department of Otorhinolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan
- *Correspondence: Yao-Te Tsai,
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18
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Yang H, Zhang J, Ling J. The Modulatory Effects and Targets Prediction of Herbal Medicines or Phytochemicals on Cancer Immunosurveillance. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2022; 50:1401-1422. [PMID: 35748216 DOI: 10.1142/s0192415x22500604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Cancer is a main life-threatening disease worldwide. Due to the adverse effects of conventional chemotherapies and radiotherapies, immunotherapy has emerged as a potent strategy to treat cancer. In cancer immunotherapy, cancer immune surveillance plays a crucial role in the cancer process, which contains various effector cells from innate and adaptive immunity. This review summarized the functions of innate and adaptive immune cells in cancer immunosurveillance and their main reported targets. Moreover, the potential targets about the modulatory effects of cancer immunosurveillance were predicted using network-based target analysis, with total predicted pathways not only reporting previously reported pathways, but also putative signaling pathways pending for investigation. In addition, the potential use of herbal medicines and their phytochemicals in the modulation of cancer immunosurveillance were also discussed. Taken together, this review paper aims to provide scientific insight into further drug development, particularly herbs, phytochemicals, and TCM formulae, in the modulatory effects of cancer immunosurveillance.
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Affiliation(s)
- Huihai Yang
- College of Chinese Medicine Material, Jilin Agricultural University, Changchun 136000, P. R. China
- Institute of Chinese Medicine, State Key Laboratory of Research on Bioactivities, Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Jing Zhang
- College of Chinese Medicine Material, Jilin Agricultural University, Changchun 136000, P. R. China
| | - Jiawei Ling
- Institute of Chinese Medicine, State Key Laboratory of Research on Bioactivities, Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
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19
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Hadjigol S, Shah BA, O’Brien-Simpson NM. The 'Danse Macabre'-Neutrophils the Interactive Partner Affecting Oral Cancer Outcomes. Front Immunol 2022; 13:894021. [PMID: 35784290 PMCID: PMC9243430 DOI: 10.3389/fimmu.2022.894021] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 05/12/2022] [Indexed: 12/11/2022] Open
Abstract
Over the past few decades, tremendous advances in the prevention, diagnosis, and treatment of cancer have taken place. However for head and neck cancers, including oral cancer, the overall survival rate is below 50% and they remain the seventh most common malignancy worldwide. These cancers are, commonly, aggressive, genetically complex, and difficult to treat and the delay, which often occurs between early recognition of symptoms and diagnosis, and the start of treatment of these cancers, is associated with poor prognosis. Cancer development and progression occurs in concert with alterations in the surrounding stroma, with the immune system being an essential element in this process. Despite neutrophils having major roles in the pathology of many diseases, they were thought to have little impact on cancer development and progression. Recent studies are now challenging this notion and placing neutrophils as central interactive players with other immune and tumor cells in affecting cancer pathology. This review focuses on how neutrophils and their sub-phenotypes, N1, N2, and myeloid-derived suppressor cells, both directly and indirectly affect the anti-tumor and pro-tumor immune responses. Emphasis is placed on what is currently known about the interaction of neutrophils with myeloid innate immune cells (such as dendritic cells and macrophages), innate lymphoid cells, natural killer cells, and fibroblasts to affect the tumor microenvironment and progression of oral cancer. A better understanding of this dialog will allow for improved therapeutics that concurrently target several components of the tumor microenvironment, increasing the possibility of constructive and positive outcomes for oral cancer patients. For this review, PubMed, Web of Science, and Google Scholar were searched for manuscripts using keywords and combinations thereof of "oral cancer, OSCC, neutrophils, TANs, MDSC, immune cells, head and neck cancer, and tumor microenvironment" with a focus on publications from 2018 to 2021.
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Affiliation(s)
- Sara Hadjigol
- ACTV Research Group, Division of Basic and Clinical Oral Sciences, Centre for Oral Health Research, Melbourne Dental School, Royal Dental Hospital, The University of Melbourne, Carlton, VIC, Australia
| | | | - Neil M. O’Brien-Simpson
- ACTV Research Group, Division of Basic and Clinical Oral Sciences, Centre for Oral Health Research, Melbourne Dental School, Royal Dental Hospital, The University of Melbourne, Carlton, VIC, Australia
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20
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Zhang Z, Bu L, Luo J, Guo J. Targeting protein kinases benefits cancer immunotherapy. Biochim Biophys Acta Rev Cancer 2022; 1877:188738. [PMID: 35660645 DOI: 10.1016/j.bbcan.2022.188738] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/16/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023]
Abstract
Small-molecule kinase inhibitors have been well established and successfully developed in the last decades for cancer target therapies. However, intrinsic or acquired drug resistance is becoming the major barrier for their clinical application. With the development of immunotherapies, in particular the discovery of immune checkpoint inhibitors (ICIs), the combination of ICIs with other therapies have recently been extensively explored, among which combination of ICIs with kinase inhibitors achieves promising clinical outcome in a plethora of cancer types. Here we comprehensively summarize the potent roles of protein kinases in modulating immune checkpoints both in tumor and immune cells, and reshaping tumor immune microenvironments by evoking innate immune response and neoantigen generation or presentation. Moreover, the clinical trial and approval of combined administration of kinase inhibitors with ICIs are collected, highlighting the precise strategies to benefit cancer immune therapies.
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Affiliation(s)
- Zhengkun Zhang
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Lang Bu
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junhang Luo
- Department of Urology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
| | - Jianping Guo
- Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
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21
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Yang H, Wang L, Zhang J. Leukocyte modulation by natural products from herbal medicines and potential as cancer immunotherapy. J Leukoc Biol 2022; 112:185-200. [PMID: 35612275 DOI: 10.1002/jlb.3ru0222-087rrr] [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: 02/03/2022] [Revised: 04/15/2022] [Indexed: 12/13/2022] Open
Abstract
Cancer constitutes a kind of life-threatening disease that is prevalent throughout the world. In light of limitations in conventional chemotherapies or radiotherapies, cancer immunotherapy has emerged as a potent strategy in treating cancer. In cancer immunotherapy, preliminary studies have demonstrated that cancer immune surveillance serves a crucial role in tumor initiation, progression, and metastasis. Herbal medicines and natural products, which serve as alternative medicines, are involved in the modulation of tumor immunosurveillance to enhance antitumor activity. Accordingly, this review aimed to summarize the modulation function of herbal medicines and natural products on tumor immunosurveillance while providing scientific insight into further research on its molecular mechanism and potential clinical applications.
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Affiliation(s)
- Huihai Yang
- Department of Chinese Medicine, College of Chinese Medicine Material, Jilin Agricultural University, Changchun, China.,Department of Chinese medicine, College of Medicine, Changchun Science-Technology University, Changchun, China.,Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Lulu Wang
- Department of Chinese medicine, College of Medicine, Changchun Science-Technology University, Changchun, China
| | - Jing Zhang
- Department of Chinese Medicine, College of Chinese Medicine Material, Jilin Agricultural University, Changchun, China
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22
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Chu Y, Qian L, Ke Y, Feng X, Chen X, Liu F, Yu L, Zhang L, Tao Y, Xu R, Wei J, Liu B, Liu Q. Lymph node-targeted neoantigen nanovaccines potentiate anti-tumor immune responses of post-surgical melanoma. J Nanobiotechnology 2022; 20:190. [PMID: 35418151 PMCID: PMC9006542 DOI: 10.1186/s12951-022-01397-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/23/2022] [Indexed: 12/17/2022] Open
Abstract
Background Neoantigens are considered ideal targets for immunotherapy, especially tumor vaccine, because of their strong specificity and immunogenicity. Here, we developed a neoantigen nanovaccine used liposomes with lymph-node targeting characteristic. Methods Our nanovaccine was composed of neoantigens, an amphiphilic liposome and an adjuvant Montanide™ ISA 51. Small animal imaging system and immunofluorescence staining were used to identify the distribution of nanovaccines. A subcutaneous-tumor-resection mouse model of melanoma was established to evaluate the anti-tumor efficacy. Flow cytometry was performed to assay the immune responses initiated by nanovaccines. Results Nanovaccines could traffic to lymph nodes, be uptaken by CD11c+ DCs and promote DCs maturity. After the treatment of our neoantigen nanovaccines, the average recurrence time was extended from 11 to 16 days and the median survival time was even prolonged 7.5 days relative to the control group (NS group). Nanovaccines increased neoantigen-specific T cells to 10-fold of free vaccines, and upregulated Th1 cytokines, such as IFN-γ and TNF-α. The anti-tumor activity of spleen lymphocytes in the nanovaccine group was significantly stronger than that of other groups. However, some immune-inhibitory cells or molecules in tumor microenvironment have been detected upregulated under the immune pressure of neoantigen nanovaccines, such as Tregs and PD-L1. The efficacy of the neoantigen nanovaccine combined with anti-PD1 antibody or Treg inhibiting peptide P60 was better than that of the single treatment. Conclusions We developed a general vaccine strategy, triggering specific T cell responses, and provided feasible combination strategies for better anti-tumor efficacy. Graphical abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-022-01397-7.
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Affiliation(s)
- Yanhong Chu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Lingyu Qian
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.,Department of Oncology, Rudong Peoples' Hospital of Jiangsu Province, Nantong, China
| | - Yaohua Ke
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Xiaoyu Feng
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Xinjie Chen
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Fangcen Liu
- Department of Pathology, Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Lixia Yu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Lianru Zhang
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Yaping Tao
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Rui Xu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Jia Wei
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Qin Liu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
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23
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Tagkareli S, Salagianni M, Galani I, Manioudaki M, Pavlos E, Thanopoulou K, Andreakos E. CD103 integrin identifies a high IL-10-producing FoxP3 + regulatory T-cell population suppressing allergic airway inflammation. Allergy 2022; 77:1150-1164. [PMID: 34658046 DOI: 10.1111/all.15144] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/10/2021] [Accepted: 10/03/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Although FoxP3+ regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the disease context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders. The present study aimed at characterizing distinct FoxP3+ Treg subpopulations involved in the suppression of Th2-mediated allergic inflammation in the lung. METHODS We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+ Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock-in mouse model (Foxp3cre Cd103dtr ) enabling the specific ablation of CD103+ FoxP3+ Tregs for functional studies. RESULTS We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+ Treg cells expressed the integrin CD103 which marks FoxP3+ Treg cells of high IL-10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2-mediated inflammatory responses. CD103+ FoxP3+ Tregs were essential for keeping allergic inflammation under control as their specific depletion in Foxp3cre Cd103dtr mice lead to severe alveocapillary damage, eosinophilic pneumonia, and markedly reduced lifespan of the animals. Conversely, adoptive transfer of CD103+ FoxP3+ Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL-10-dependent manner. CONCLUSIONS Our study identifies a novel regulatory T-cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.
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Affiliation(s)
- Sofia Tagkareli
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Maria Salagianni
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Ioanna‐Evdokia Galani
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Maria Manioudaki
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Eleftherios Pavlos
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Kalliopi Thanopoulou
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
| | - Evangelos Andreakos
- Laboratory of Immunobiology Center for Clinical, Experimental Surgery and Translational ResearchBiomedical Research Foundation of the Academy of Athens Athens Greece
- Airway Disease Infection Section National Heart and Lung InstituteImperial College London London UK
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24
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Khalifa R, Elsese N, El-Desouky K, Shaair H, Helal D. Immune checkpoint proteins (PD-L1 and CTLA-4) in endometrial carcinoma: prognostic role and correlation with CD4 +/CD8 + tumor infiltrating lymphocytes (TILs) ratio. J Immunoassay Immunochem 2021; 43:192-212. [PMID: 34697997 DOI: 10.1080/15321819.2021.1981377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Developing the prognostic aspects of endometrial carcinoma through shedding light on immune check point proteins (PD-L1 and CTLA-4) together with Tumor-Infiltrating Lymphocytes (TILs) may help finding new targets for immunotherapy, especially for advanced cases. This study aimed to study the immunohistochemical expression of PD-L1 and CTLA-4 in correlation with tumor infiltrating lymphocytes (TILs) in series of endometrial carcinomas. CTLA-4 showed notably higher frequency of expression in the studied cases than PD-L1. However, both showed significant association across different histopathological subtypes. PD-L1 immunohistochemical expression in studied endometrial carcinomas was significantly associated with low CD4+/CD8+ratio, high tumor grades, presence of lymph node metastasis and higher tumor stage. CTLA-4 immunohistochemical expression in studied endometrial carcinomas was significantly associated with low CD4+/CD8+ ratio and high tumor grades but not with tumor stage. Both PD-L1 & CTLA-4 are expressed in subset of endometrial carcinomas with more prevalence of the latter. Both immune checkpoint proteins have significant correlation with different prognostic clinicopathological parameters together with TILs (CD4 & CD8 and their ratio). Increased activated cytotoxic T lymphocytes and PD-L1 expression in endometrial carcinomas may suggest identification of patients' subset of tumors that can be candidates for treatment with immunotherapy.
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Affiliation(s)
- Rana Khalifa
- Department of pathology, Faculty of Medicine, Pathology, Tanta University, Tanta, Egypt
| | - Nawal Elsese
- Department of pathology, Faculty of Medicine, Pathology, Tanta University, Tanta, Egypt
| | - Karima El-Desouky
- Department of pathology, Faculty of Medicine, Pathology, Tanta University, Tanta, Egypt
| | - Hassan Shaair
- Department of pathology, Faculty of Medicine, Pathology, Tanta University, Tanta, Egypt
| | - Duaa Helal
- Department of pathology, Faculty of Medicine, Pathology, Tanta University, Tanta, Egypt
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25
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Paşcalău AV, Cheregi CD, Mureşan MŞ, Şandor MI, Huniadi CA, Nikin Z, Judea Pusta CT, Bodog FD, Ionescu C, Pop OL. CD4+ CD25+ regulatory T-cells role in tumor microenvironment of the squamous cell carcinoma. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 62:249-253. [PMID: 34609428 PMCID: PMC8597358 DOI: 10.47162/rjme.62.1.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Introduction: Squamous cell carcinoma (SCC) is the most common skin cancer with a high rate of death. Different lymphocyte populations play an important role in modulating the immune response in the tumor microenvironment. The increase in the proportion of cluster of differentiation (CD)4+ CD25+ regulatory T-cell (Treg) lymphocytes is associated, in different studies, with the increase of the cell multiplication rate. Aim: To analyze the Treg lymphocyte subpopulations and to correlate the results with the presence of the CD8+ cytotoxic T-cell (Tc) lymphocyte population. Materials and Methods: Sixty primary skin SCC specimens were incubated with anti-CD8 (clone SP57) rabbit monoclonal antibody and anti-CD25 (clone 4C9) mouse monoclonal antibody. Results: The ratio of the intratumoral/peritumoral CD4+ CD25+ forkhead box protein p3 (Foxp3) lymphocytes was 0.46, emphasizing that at tumor margins, where tumor aggressiveness is higher, these lymphocytes subpopulations facilitate tumor progression. The comparative analysis of the tumor microenvironment profile revealed that in the case of intratumoral immune response, the number of Tc-type lymphocytes (CD8+) was 3.34 times higher compared to Treg lymphocytes (p<0001). In the peritumoral area, the number of Tc lymphocytes was 5.05 times higher compared to Treg lymphocytes (p<0001). Conclusions: Treg lymphocytes inhibition may cause the suppression of the antitumoral cell immune response in the tumor environment. We believe that Treg lymphocytes should represent a focus of interest for a new personalized therapy. New studies are needed to better understand the immune response in the tumor microenvironment.
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Affiliation(s)
- Andrei Vasile Paşcalău
- Department of Surgical Disciplines, Department of Morphological Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, Romania; ,
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26
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Anti-Cancer Treatment Strategies in the Older Population: Time to Test More? Geriatrics (Basel) 2021; 6:geriatrics6020042. [PMID: 33921136 PMCID: PMC8167638 DOI: 10.3390/geriatrics6020042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/12/2021] [Accepted: 04/13/2021] [Indexed: 12/29/2022] Open
Abstract
Aging is a well-recognized risk factor for the development of cancer. The incidence of new cancer diagnoses has increased globally given the rising senior population. Many hypotheses for this increased risk have been postulated over decades, including increased genetic and epigenetic mutations and the concept of immunosenescence. The optimal treatment strategies for this population with cancer are unclear. Older cancer patients are traditionally under-represented in clinical trials developed to set the standard of care, leading to undertreatment or increased toxicity. With this background, it is crucial to investigate new opportunities that belong to the most recent findings of an anti-cancer agent, such as immune-checkpoint inhibitors, to manage these daily clinical issues and eventually combine them with alternative administration strategies of antiblastic drugs such as metronomic chemotherapy.
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27
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Donkor MK, Sarkar A, Li MO. Tgf-β1 produced by activated CD4(+) T Cells Antagonizes T Cell Surveillance of Tumor Development. Oncoimmunology 2021; 1:162-171. [PMID: 22720237 PMCID: PMC3376999 DOI: 10.4161/onci.1.2.18481] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
TGFβ1 is a regulatory cytokine with a crucial function in the control of T cell tolerance to tumors. Our recent study revealed that T cell-produced TGFβ1 is essential for inhibiting cytotoxic T cell responses to tumors. However, the exact TGFβ1-producing T cell subset required for tumor immune evasion remains unknown. Here we showed that deletion of TGFβ1 from CD8+ T cells or Foxp3+ regulatory T (Treg) cells did not protect mice against transplanted tumors. However, absence of TGFβ1 produced by activated CD4+ T cells and Treg cells inhibited tumor growth, and protected mice from spontaneous prostate cancer. These findings suggest that TGFβ1 produced by activated CD4+ T cells is a necessary requirement for tumor evasion from immunosurveillance.
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Affiliation(s)
- Moses K Donkor
- Immunology Program; Memorial Sloan-Kettering Cancer Center; New York, NY USA
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28
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Rana J, Biswas M. Regulatory T cell therapy: Current and future design perspectives. Cell Immunol 2020; 356:104193. [PMID: 32823038 DOI: 10.1016/j.cellimm.2020.104193] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/30/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023]
Abstract
Regulatory T cells (Tregs) maintain immune equilibrium by suppressing immune responses through various multistep contact dependent and independent mechanisms. Cellular therapy using polyclonal Tregs in transplantation and autoimmune diseases has shown promise in preclinical models and clinical trials. Although novel approaches have been developed to improve specificity and efficacy of antigen specific Treg based therapies, widespread application is currently restricted. To date, design-based approaches to improve the potency and persistence of engineered chimeric antigen receptor (CAR) Tregs are limited. Here, we describe currently available Treg based therapies, their advantages and limitations for implementation in clinical studies. We also examine various strategies for improving CAR T cell design that can potentially be applied to CAR Tregs, such as identifying co-stimulatory signalling domains that enhance suppressive ability, determining optimal scFv affinity/avidity, and co-expression of accessory molecules. Finally, we discuss the importance of tailoring CAR Treg design to suit the individual disease.
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Affiliation(s)
- Jyoti Rana
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Moanaro Biswas
- Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
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29
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Wang W, Thomas R, Sizova O, Su DM. Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity - A Mini-Review. Front Immunol 2020; 11:773. [PMID: 32425946 PMCID: PMC7203483 DOI: 10.3389/fimmu.2020.00773] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/06/2020] [Indexed: 12/14/2022] Open
Abstract
The thymus is the central lymphoid organ for T cell development, a cradle of T cells, and for central tolerance establishment, an educator of T cells, maintaining homeostatic cellular immunity. T cell immunity is critical to control cancer occurrence, relapse, and antitumor immunity. Evidence on how aberrant thymic function influences cancer remains largely insufficient, however, there has been recent progress. For example, the involuted thymus results in reduced output of naïve T cells and a restricted T cell receptor (TCR) repertoire, inducing immunosenescence and potentially dampening immune surveillance of neoplasia. In addition, the involuted thymus relatively enhances regulatory T (Treg) cell generation. This coupled with age-related accumulation of Treg cells in the periphery, potentially provides a supportive microenvironment for tumors to escape T cell-mediated antitumor responses. Furthermore, acute thymic involution from chemotherapy can create a tumor reservoir, resulting from an inflammatory microenvironment in the thymus, which is suitable for disseminated tumor cells to hide, survive chemotherapy, and become dormant. This may eventually result in cancer metastatic relapse. On the other hand, if thymic involution is wisely taken advantage of, it may be potentially beneficial to antitumor immunity, since the involuted thymus increases output of self-reactive T cells, which may recognize certain tumor-associated self-antigens and enhance antitumor immunity, as demonstrated through depletion of autoimmune regulator (AIRE) gene in the thymus. Herein, we briefly review recent research progression regarding how altered thymic function modifies T cell immunity against tumors.
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Affiliation(s)
- Weikan Wang
- Cell Biology, Immunology, and Microbiology Graduate Program, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Rachel Thomas
- Cell Biology, Immunology, and Microbiology Graduate Program, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, TX, United States
| | - Olga Sizova
- Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Dong-Ming Su
- Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States
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30
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Drokov M, Davydova Y, Popova N, Kapranov N, Starikova O, Mikhaltsova E, Nareyko M, Dmitrova A, Konova Z, Galtseva I, Kuzmina L, Parovichnikova E, Savchenko V. High expression of granzyme B in conventional CD4+ T cells is associated with increased relapses after allogeneic stem cells transplantation in patients with hematological malignancies. Transpl Immunol 2020; 65:101295. [PMID: 32302642 DOI: 10.1016/j.trim.2020.101295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 04/13/2020] [Accepted: 04/13/2020] [Indexed: 11/26/2022]
Abstract
Granzyme B is known to be a serine protease contained in granules of cytotoxic T cells. We have previously reported an influence of granzyme B expression in T regulatory cells (Tregs) on the risk of acute graft versus host disease (GVHD) onset. However, it is still unknown if conventional T cells (Tcon) use the granzyme B pathway as a mechanism of alloimmunity. We hypothesized that granzyme B in Tcon may affect recurrence within the first 6 months after allogeneic transplantation (allo-HSCT). A total of 65 patients with different hematological malignancies were included in this study. Blood samples were collected on day +30 after allo-HSCT. The percentage of granzyme B positive conventional T cells in patients who developed relapse in the first 6 months after allo-HSCT was 11.3 (4.5-35.3) compared to the others in continuous complete remission-1.3 (3.65-9.7), р = 0.011. The risk of relapse after allo-HSCT was in 3.9 times higher in patients with an increased percentage of granzyme B positive conventional T cells. The findings demonstrated that the percentage of granzyme B positive conventional T cells on day +30 after allo-HSCT could be a predictable marker of relapse within the first 6 months after allo-HSCT.
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Affiliation(s)
- Mikhail Drokov
- Immunotherapy and Post-BMT Complications Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation.
| | - Yulia Davydova
- Flow Cytometry Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Natalia Popova
- Immunotherapy and Post-BMT Complications Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Nikolay Kapranov
- Flow Cytometry Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Olga Starikova
- Immunotherapy and Post-BMT Complications Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Ekaterina Mikhaltsova
- Immunotherapy and Post-BMT Complications Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Maria Nareyko
- BMT Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Anna Dmitrova
- Immunotherapy and Post-BMT Complications Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Zoya Konova
- BMT Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Irina Galtseva
- Flow Cytometry Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Larisa Kuzmina
- BMT Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Elena Parovichnikova
- BMT Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
| | - Valery Savchenko
- BMT Department, National Research Center for Hematology, Noviy Zikovskiy proezd 4, 125167 Moscow, Russian Federation
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31
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Takaku S, Shimizu M, Takahashi H. Japanese Kampo Medicine Juzentaihoto Enhances Antitumor Immunity in CD1d -/- Mice Lacking NKT Cells. Integr Cancer Ther 2020; 19:1534735419900798. [PMID: 31959018 PMCID: PMC6974754 DOI: 10.1177/1534735419900798] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Although the Japanese traditional herbal medicine (Kampo), Juzentaihoto (JTT),
has been reported to have antitumor effects in several tumor models, its role in
tumor immunology remains controversial. In the present study, we tested whether
oral administration of JTT enhances antitumor immunity in CD1d−/−
mice, in which immunosuppression was partially relieved due to the lack of NKT
cells. In a subcutaneous murine syngeneic CT26 colorectal tumor model, JTT had
no impact on tumor growth in wild type (WT) BALB/c mice. However, the growth
rate of tumors was significantly slower in CD1d−/− mice than in WT
mice. Surprisingly, JTT significantly delayed tumor growth in such
CD1d−/− mice. In vivo depletion of CD8+ T cells
revealed that CD8+ T cells are required for JTT’s antitumor activity.
Moreover, tumor-reactive cytotoxic T-lymphocytes were detected exclusively in
JTT-treated mice with well-controlled tumors. JTT did not affect the number of
tumor-infiltrating CD4+ regulatory T cells. On the contrary, JTT
increased the degranulation marker CD107a+ CD8+ T cells
and decreased Ly6G+ Ly6Clo polymorphonuclear
myeloid-derived suppressor cells in tumor-infiltrating lymphocytes, most
probably contributing to the suppression of tumor growth in JTT-treated mice.
Nonetheless, JTT had no impact on the proportion of monocytic myeloid-derived
suppressor cells. In conclusion, our results indicate that in the absence of NKT
cells, JTT augments antitumor immunity by CD8+ T cells, suggesting
that this Kampo medicine is a promising anticancer adjuvant when negative immune
regulation is partially relieved.
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Affiliation(s)
- Shun Takaku
- Department of Microbiology and Immunology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Masumi Shimizu
- Department of Microbiology and Immunology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
| | - Hidemi Takahashi
- Department of Microbiology and Immunology, Nippon Medical School, Bunkyo-ku, Tokyo, Japan
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32
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Zhang DY, Chen W, Zhang HY, Lv SQ, Lu XN, Tao YP, Zhang M, Liu JF, Yang M, Qiao YL, Braithwaite D. Cervical neoplastic lesions in relation to CD4 T-lymphocyte counts and antiretroviral therapy among women with clinical stage 1 HIV in Yunnan, China. Kaohsiung J Med Sci 2020; 36:450-459. [PMID: 31913555 DOI: 10.1002/kjm2.12175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 12/08/2019] [Indexed: 12/13/2022] Open
Abstract
China lacks data demonstrating associations of cervical neoplastic lesions with CD4 T-lymphocyte (CD4 cell) counts and antiretroviral therapy (ART) among HIV-infected women, suggesting relevant investigations are needed. A total of 545 HIV-infected women were enrolled in Yunnan, China, between 2011 and 2013. CD4 cell counts and ART were measured via medical records and cervical neoplastic lesions were measured by professional pathologists. Multivariable logistic models, which treated cervical intraepithelial neoplasia (CIN) 1+ and CIN2+ as outcomes, calculated adjusted odds ratio (aOR) of CD4 cell counts and ART. Subgroup analysis treating CIN1+ as the outcome was conducted by HIV infection duration (<4 vs ≥4 years), ethnicity (Han vs non-Han), and study site (Mangshi vs Kunming). The prevalence of CIN1+ and CIN2+ was 17.4% and 7.3%, respectively. Overall, 243 (44.6%) women had CD4 cell counts ≥500 cell/μL, 187 (34.3%) used ART for less than 2 years, and 236 (43.3%) used ART for at least 2 years. We found inverse associations of CIN1+ with CD4 cell counts (≥500 compared to <500 cells/μL: aOR = 0.46, 95% CI = 0.27-0.79) and ART use (<2 years: aOR = 0.43, 95% CI = 0.21-0.87; ≥2 years: aOR = 0.54, 95% CI = 0.27-1.10). Point estimates did not change substantially for CIN2+ but aORs of ART became nonsignificant. No significant interaction was observed for HIV infection duration. We found significant interaction between CD4 cell counts and ethnicity and study site in relation to CIN1+. Our study suggests potential protective effects of high CD4 cell counts against cervical neoplastic lesions among HIV-infected women, whereas associations of ART are less consistent.
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Affiliation(s)
- Dong-Yu Zhang
- Department of Oncology, Georgetown University School of Medicine, Washington, District of Columbia
| | - Wen Chen
- Department of Cancer Epidemiology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hong-Yun Zhang
- Department of Obstetrics and Gynecology, Kunming Medical University, Kunming, China
| | - Song-Qin Lv
- Department of Obstetrics and Gynecology, Kunming Medical University, Kunming, China
| | - Xiao-Ning Lu
- Department of Obstetrics and Gynecology, Kunming Medical University, Kunming, China
| | - Yan-Ping Tao
- Department of Obstetrics and Gynecology, Kunming Medical University, Kunming, China
| | - Mi Zhang
- Department of HIV/AIDS Clinical Research, Yunnan Provincial Hospital of Infectious Disease, AIDS Care Center (YNACC), Kunming, China
| | - Jia-Fa Liu
- Department of HIV/AIDS Clinical Research, Yunnan Provincial Hospital of Infectious Disease, AIDS Care Center (YNACC), Kunming, China
| | - Min Yang
- Department of Epidemiology, University of North Carolina at Chapel Hill Gillings School of Global Public Health, Chapel Hill, North Carolina
| | - You-Lin Qiao
- Department of Cancer Epidemiology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dejana Braithwaite
- Department of Oncology, Georgetown University School of Medicine, Washington, District of Columbia
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33
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Hashemi V, Maleki LA, Esmaily M, Masjedi A, Ghalamfarsa G, Namdar A, Yousefi M, Yousefi B, Jadidi-Niaragh F. Regulatory T cells in breast cancer as a potent anti-cancer therapeutic target. Int Immunopharmacol 2019; 78:106087. [PMID: 31841758 DOI: 10.1016/j.intimp.2019.106087] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/23/2019] [Accepted: 11/25/2019] [Indexed: 02/08/2023]
Abstract
Despite marked advances in treatment approaches, breast cancer is still going to be more prevalent, worldwide. High levels of regulatory T (Treg) cells have repeatedly been demonstrated in circulation, lymph nodes, and tumor samples from patients with various cancer types. The transcription factor Forkhead box protein 3 (Foxp3)-expressing Treg cells have the high suppressive potential of the immune system and are fundamental in preserving immune homeostasis and self-tolerance. However, they enhance tumor development by curbing efficient anti-tumor immune mechanisms in malignancies. Moreover, the accumulation of Treg cells in breast tumors is related to the short overall survival of patients. Treg cell frequency has been applied as an independent predicting factor to diagnose patients with a high risk of relapse. Pulling out all populations of Treg cells to promote the efficacy of anticancer treatment methods may potentially lead to hazardous autoimmune disorders. Thus, realizing the exact structure of tumor-infiltrating Treg cells is pivotal to efficiently target Treg cells in tumors. There are exclusive and non-exclusive approaches to lower down and degrade the number/function of Treg cells. These approaches can include inhibiting tumoral migration, depletion, interference with function, and utilizing T cell plasticity. This review article attempts to clarify the implications concerning the involvement of Treg cells in breast cancer progression and discuss the current approaches in the treatment of this cancer via modulation of Treg cells function.
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Affiliation(s)
- Vida Hashemi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Basic Science, Faculty of Medicine, Maragheh University of Medical Sciences, Maragheh, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Maryam Esmaily
- Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Masjedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ghasem Ghalamfarsa
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Afshin Namdar
- Katz Group Centre for Pharmacy and Health Research, University of Alberta, Edmonton, Canada
| | - Mehdi Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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34
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Abstract
The enhanced understanding of immunology experienced over the last 4 decades afforded through the tools of molecular biology has recently translated into cancer immunotherapy becoming one of the most exciting and rapidly expanding fields. Human cancer immunotherapy is now recognized as one of the pillars of treatment alongside surgery, radiation, and chemotherapy. The field of veterinary cancer immunotherapy has also rapidly advanced in the last decade with a handful of commercially available products and a plethora of investigational cancer immunotherapies that will hopefully expand the veterinary oncology treatment toolkit over time.
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35
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Wu J, Ma S, Hotz-Wagenblatt A, Angel P, Mohr K, Schlimbach T, Schmitt M, Cui G. Regulatory T cells sense effector T-cell activation through synchronized JunB expression. FEBS Lett 2019; 593:1020-1029. [PMID: 31017652 DOI: 10.1002/1873-3468.13393] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/15/2019] [Accepted: 04/16/2019] [Indexed: 01/05/2023]
Abstract
To maintain immune tolerance, effector T-cell (Teff) responses must be checked by the regulatory T cells (Tregs) in time. It remains incompletely understood how Tregs sense real-time Teff activation. Here, we report that the AP-1 transcription factor JunB, which is induced in Teffs upon T-cell receptor (TCR) activation, is also increased in Tregs by TCR stimuli. Treg-specific deletion of Junb impairs Treg identity, causes uncontrolled inflammatory cytokine production by Teffs and leads to the T-box transcription factor T-bet-dependent spontaneous inflammation. Furthermore, JunB deficiency in Tregs unleashes antitumor Teff responses in a mouse model of melanoma. We conclude that JunB alarms Tregs of the emerging Teff activation and synchronizes immune regulation with the immune reaction in autoimmunity and cancer.
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Affiliation(s)
- Jingxia Wu
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sicong Ma
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Medical Faculty Heidelberg, Heidelberg University, Germany
| | - Agnes Hotz-Wagenblatt
- Core Facility Omics IT and Data Management, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Angel
- Division Signal Transduction and Growth Control (A100), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Kerstin Mohr
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilo Schlimbach
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Schmitt
- Medical Faculty Heidelberg, Heidelberg University, Germany.,Internal Medicine V, University Heidelberg Hospital, Germany
| | - Guoliang Cui
- T Cell Metabolism Group (D140), German Cancer Research Center (DKFZ), Heidelberg, Germany.,Faculty of Biosciences, Heidelberg University, Germany
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36
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Gliwiński M, Piotrowska M, Iwaszkiewicz-Grześ D, Urban-Wójciuk Z, Trzonkowski P. Therapy with CD4 +CD25 + T regulatory cells - should we be afraid of cancer? Contemp Oncol (Pozn) 2019; 23:1-6. [PMID: 31061630 PMCID: PMC6500397 DOI: 10.5114/wo.2019.84110] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 03/24/2019] [Indexed: 12/27/2022] Open
Abstract
This review focuses on the role of regulatory T cells (Tregs) in the process of carcinogenesis. The controversy of this issue arose due to the increasing therapeutic use of Tregs in humans (inter alia, in the treatment of autoimmune diseases). It is mainly due to potential dangers related to immunosuppressive activity of these cells, especially regarding cancer. The natural function of regulatory T cells (which is the suppression of excessive activity of the immune system) is purportedly linked to an increased risk of cancer initiation. This work brings together and summarizes the most important reports of researchers dealing with this problem and attempts to explain doubts and fears related to Tregs and their uncertain connection with cancer initiation and progression. It is clearly shown that regulatory T cells are associated with acceleration of existing tumors (they are attracted by microenvironments created by cancer cells) but cannot initiate them on their own.
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Affiliation(s)
- Mateusz Gliwiński
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
| | | | | | - Zuzanna Urban-Wójciuk
- International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdansk, Gdansk, Poland
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Kara İ, Çağlı S, Vural A, Yüce İ, Gündoğ M, Deniz K, Kökoğlu K. The effect of FoxP3 on tumour stage, treatment response, recurrence and survivalability in nasopharynx cancer patients. Clin Otolaryngol 2019; 44:349-355. [PMID: 30756505 DOI: 10.1111/coa.13311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 01/27/2019] [Accepted: 02/05/2019] [Indexed: 11/28/2022]
Abstract
OBJECTIVES To investigate the relationship between the cell percentage of T regulator (Treg) cells of patients' specimens and disease severity, survivability, recurrence and metastasis in patients who were diagnosed with nasopharyngeal carcinoma (NPC). DESIGN, SETTING AND PARTICIPANTS Sixty patients who were diagnosed as NPC and treated by the same protocol were enrolled to the study. Patient files were reviewed retrospectively and their clinical and pathological results were recorded. Deparaffinized samples of nasopharyngeal carcinoma patients were stained immunohistochemically with anti-FoxP3 monoclonal antibody. All patients's Anti-FoxP3 stained slides were evaluated by the same pathologist. Stained Treg lymphocytes around the tumoral foci were investigated. Patients were divided into two groups according to the total anti-FoxP3-stained Treg cell counts of the specimens; that is, less than 20% of the total or more than 20% of the total. These groups were compared statistically. MAIN OUTCOME MEASURES Intensity of FoxP3 which is related to negative tumor response was the main outcome measure. It was evaluated in terms of stage, survival, recurrence and metastasis. RESULTS The study group consisted of 42 male patients (70%) and 18 female patients (30%). The mean age was 47 ± 14.9. NPC subtypes among the patients were undifferentiated non-keratinized type in 54 patients (90%), differentiated non-keratinized type in 4 patients (6.66%) and keratinized type squamous cell carcinoma (SCC) in 2 patients (3.33%). When the two groups were compared in terms of pathological subtype, there was no significant variation between the two groups. There was also no significant variation between the two groups when compared on the basis of tumor stage (P = 0.36 for T phase, P = 0.122 for N phase), early stage, late phase (P = 0.15), survival rate (P = 0.69 for general survival), recurrence (P = 0.2 for local recurrence, P = 0.37 for regional recurrence) and distant metastasis (P = 0.3). CONCLUSION There was no significant relationship between the concentration of these cells in the stained specimens and the disease stage, survival rate, recurrence and distant metastasis discovered.
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Affiliation(s)
- İrfan Kara
- ENT Clinic, Besni State Hospital, Adıyaman, Turkey
| | - Sedat Çağlı
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Alperen Vural
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - İmdat Yüce
- Department of Otolaryngology - Head and Neck Surgery, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Mete Gündoğ
- Department of Radiation Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Kemal Deniz
- Department of Pathology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Kerem Kökoğlu
- ENT Clinic, Develi HMK State Hospital, Kayseri, Turkey
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Chen Y, Sun J, Huang Y, Lu B, Li S. Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents. Mol Pharm 2018; 15:5162-5173. [PMID: 30222360 DOI: 10.1021/acs.molpharmaceut.8b00717] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
It is highly demanded and still a big challenge to develop an effective formulation for immunochemotherapy against advanced tumors. We have previously reported a PEG-NLG-based immunostimulatory nanocarrier (PEG2k-Fmoc-NLG919) for co-delivery of an IDO1 inhibitor (NLG919) and a chemotherapeutic agent (paclitaxel, PTX). Although antitumor immune responses were enhanced with a PTX-loaded nanocarrier, the accumulation of myeloid-derived suppressor cells (MDSCs) was also significantly increased, which may limit the overall efficacy of therapy. In the present work, we developed an improved dual-functional nanocarrier (PEG5k-Fmoc-NLG2) to co-load PTX and sunitinib (SUN, a multitarget receptor tyrosine kinase inhibitor) for improved cancer immunochemotherapy. We found that the recruited MDSCs negatively impacted the overall antitumor activity of the PTX-loaded PEG-NLG nanocarrier. Mechanistic study suggests that this is likely attributed to the PTX-mediated induction of a number of chemokines that are involved in the recruitment of MDSCs. We have further shown that the induction of these chemokines was drastically blocked by SUN. Co-delivery of PTX and SUN via the PEG5k-Fmoc-NLG9192 nanocarrier led to a further improvement in the therapeutic efficacy with a concomitant reduction in MDSCs.
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Affiliation(s)
- Yichao Chen
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States
| | - Jingjing Sun
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States
| | - Yixian Huang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States
| | - Binfeng Lu
- Department of Immunology , University of Pittsburgh School of Medicine , 200 Lothrop Street , Pittsburgh , Pennsylvania 15261 , United States
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States
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Shen M, Kang Y. Complex interplay between tumor microenvironment and cancer therapy. Front Med 2018; 12:426-439. [PMID: 30097962 DOI: 10.1007/s11684-018-0663-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 07/05/2018] [Indexed: 12/16/2022]
Abstract
Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.
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Affiliation(s)
- Minhong Shen
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA.
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Chu X, Li Y, Huang W, Feng X, Sun P, Yao Y, Yang X, Sun W, Bai H, Liu C, Ma Y. Combined immunization against TGF-β1 enhances HPV16 E7-specific vaccine-elicited antitumour immunity in mice with grafted TC-1 tumours. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:1199-1209. [PMID: 29929402 DOI: 10.1080/21691401.2018.1482306] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Therapeutic vaccine appears to be a potential approach for the treatment of human papillomavirus (HPV)-associated tumours, but its efficacy can be dampened by immunosuppressive factors such as transforming growth factor (TGF)-β1. We sought to investigate whether active immunity against TGF-β1 enhances the anti-tumour immunity elicited by an HPV16 E7-specific vaccine that we developed previously. In this study, virus-like particles of hepatitis B virus core antigen were used as vaccine carriers to deliver either TGF-β1 B cell epitopes or E7 cytotoxic T-lymphocyte epitope. The combination of preventive immunization against TGF-β1 and therapeutic immunization with the E7 vaccine significantly reduced the growth of grafted TC-1 tumours in C57 mice, showing better efficacy than immunization with only one of the vaccines. The improved efficacy of combined immunization is evidenced by elevated IFN-γ and decreased IL-4 and TGF-β1 levels in cultured splenocytes, increased E7-specific IFN-γ-expressing splenocytes, and increased numbers of CD4+IFN-γ+ and CD8+IFN-γ+ cells and decreased numbers of Treg (CD4+Foxp3+) cells in the spleen and tumours. The results strongly indicate that targeting TGF-β1 through active immunization might be a potent approach to enhancing antigen-specific therapeutic vaccine-induced anti-tumour immune efficacy and providing a combined strategy for effective cancer immunotherapy.
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Affiliation(s)
- Xiaojie Chu
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yang Li
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Weiwei Huang
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Xuejun Feng
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Pengyan Sun
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yufeng Yao
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Xu Yang
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Wenjia Sun
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Hongmei Bai
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Cunbao Liu
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
| | - Yanbing Ma
- a Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College , Kunming , China.,b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease , Kunming , China.,c Yunnan Engineering Research Center of Vaccine Research and Development on Severe Infectious Disease , Kunming , China
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Dwarakanath BS, Farooque A, Gupta S. Targeting regulatory T cells for improving cancer therapy: Challenges and prospects. Cancer Rep (Hoboken) 2018; 1:e21105. [PMID: 32729245 DOI: 10.1002/cnr2.1105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 03/22/2018] [Accepted: 04/07/2018] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Regulatory T cells (Tregs) play a central role in immune responses to infectious agents and tumors. Paradoxically, Tregs protect self-cells from the immune response as a part of peripheral tolerance and prevents autoimmune disorders, whereas during the process of carcinogenesis, they are exploited by tumor cells for protection against antitumor immune responses. Therefore, Tregs are often considered as a major obstacle in anticancer therapy. The objective of this review is to provide a current understanding on Tregs as a potential cellular target for achieving therapeutic gain and discuss various approaches that are implicated at preclinical and clinical scenario. RECENT FINDINGS Several approaches like immunotherapy and adjuvant chemotherapy, which reduce Tregs population, have been found to be useful in improving local tumor control. Our recent observations with the glycolytic inhibitor, 2-deoxy-D-glucose, established as an adjuvant in radiotherapy and chemotherapy of tumors also show that potential of 2-deoxy-D-glucose to improve local tumor control is linked with its ability to reduce the Tregs pool. CONCLUSIONS Several published studies and emerging evidences indicate that suppression of Treg numbers, infiltration into the tumors, and function can improve the cancer therapy by enhancing the antitumor immunity.
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Affiliation(s)
| | | | - Seema Gupta
- Department of Oncology, Georgetown University, Washington, DC, USA
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43
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Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, Makarev E, V Artemov A, Wysocki PT, Mehra R, Nimmagadda S, Marchionni L, Sidransky D, Borrello IM, Izumchenko E, Bedi A. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018. [PMID: 29467463 DOI: 10.1038/s41467-017-02696-6.pmid:29467463;pmcid:pmc5821872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/09/2023] Open
Abstract
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
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Affiliation(s)
- Rajani Ravi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Kimberly A Noonan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Vui Pham
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Rishi Bedi
- Department of Computer Science, Stanford University, Palo Alto, CA, 94305, USA
| | - Alex Zhavoronkov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Ivan V Ozerov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Eugene Makarev
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Artem V Artemov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Piotr T Wysocki
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Ranee Mehra
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Sridhar Nimmagadda
- Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA
| | - Luigi Marchionni
- Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Ivan M Borrello
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Evgeny Izumchenko
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Atul Bedi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
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Ravi R, Noonan KA, Pham V, Bedi R, Zhavoronkov A, Ozerov IV, Makarev E, V Artemov A, Wysocki PT, Mehra R, Nimmagadda S, Marchionni L, Sidransky D, Borrello IM, Izumchenko E, Bedi A. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nat Commun 2018; 9:741. [PMID: 29467463 PMCID: PMC5821872 DOI: 10.1038/s41467-017-02696-6] [Citation(s) in RCA: 247] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Accepted: 12/18/2017] [Indexed: 12/24/2022] Open
Abstract
A majority of cancers fail to respond to immunotherapy with antibodies targeting immune checkpoints, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1)/PD-1 ligand (PD-L1). Cancers frequently express transforming growth factor-β (TGFβ), which drives immune dysfunction in the tumor microenvironment by inducing regulatory T cells (Tregs) and inhibiting CD8+ and TH1 cells. To address this therapeutic challenge, we invent bifunctional antibody-ligand traps (Y-traps) comprising an antibody targeting CTLA-4 or PD-L1 fused to a TGFβ receptor II ectodomain sequence that simultaneously disables autocrine/paracrine TGFβ in the target cell microenvironment (a-CTLA4-TGFβRIIecd and a-PDL1-TGFβRIIecd). a-CTLA4-TGFβRIIecd is more effective in reducing tumor-infiltrating Tregs and inhibiting tumor progression compared with CTLA-4 antibody (Ipilimumab). Likewise, a-PDL1-TGFβRIIecd exhibits superior antitumor efficacy compared with PD-L1 antibodies (Atezolizumab or Avelumab). Our data demonstrate that Y-traps counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a potentially more effective immunotherapeutic strategy against cancers that are resistant to current immune checkpoint inhibitors.
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Affiliation(s)
- Rajani Ravi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Kimberly A Noonan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Vui Pham
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Rishi Bedi
- Department of Computer Science, Stanford University, Palo Alto, CA, 94305, USA
| | - Alex Zhavoronkov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Ivan V Ozerov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Eugene Makarev
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Artem V Artemov
- Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, B301, 1101 33rd Street, Baltimore, MD, 21218, USA
| | - Piotr T Wysocki
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Ranee Mehra
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Sridhar Nimmagadda
- Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA
| | - Luigi Marchionni
- Center for Computational Genomics, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - David Sidransky
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Ivan M Borrello
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Evgeny Izumchenko
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
| | - Atul Bedi
- Department of Otolaryngology-Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
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Rui T, Cheng X, Wu H, Wang F, Ye Z, Wu G. Lentiviral delivery of CTLA-4 shRNA improves the expansion of cytokine-induced killer cells and enhances cytotoxic activity in vitro. Oncol Lett 2017; 15:741-746. [PMID: 29399145 PMCID: PMC5772746 DOI: 10.3892/ol.2017.7376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 07/07/2017] [Indexed: 12/22/2022] Open
Abstract
Cytokine-induced killer (CIK) cells are in vitro-expanded cells harboring potent toxicity against tumor cells. Recently, it was identified that the cytotoxicity and proliferation of CIK cells are restricted by a prolonged CIK cell culture period. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) serves a negative role in T cell activation and proliferation. This study aims to determine whether CTLA-4 expression is associated with the inhibition of CIK cells. CIK cells were generated from peripheral blood mononuclear cells (PBMCs), and CTLA-4 shRNA (shCTLA-4) lentivirus was applied to knockdown CTLA-4 expression in CIK cells. The proliferation of CIK cells was evaluated following shCTLA-4 lentiviral transduction, and the cytotoxicity of CIK cells was investigated using the CytoTox 96 Non-Radioactive Cytotoxicity assay. The expression of CTLA-4 in CIK cells was significantly increased, compared with that in PBMCs. The shCTLA-4 lentivirus efficiently knocked down the expression of CTLA-4 in CIK cells. The shCTLA-4 lentivirus transduction of CIK cells promoted the proliferation of CIK cells in vitro (3.18±0.19-fold vs. 2.42±0.29-fold). Furthermore, the cytotoxicity of shCTLA-4 lentivirus-transduced CIK cells was significantly improved when compared with that of control shRNA lentivirus-transduced CIK cells (54.5±2.13% vs. 30.5±1.67%). Thus, the suppression of CTLA-4 expression increases cytotoxicity and ex vivo expansion of CIK cells, which indicates a clinical significance for CTLA-4 blockade in CIK cell therapy.
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Affiliation(s)
- Tao Rui
- Department of Gastroenterology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310000, P.R. China
| | - Xiangdong Cheng
- Department of Gastroenterology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310000, P.R. China
| | - Hao Wu
- Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Fuwei Wang
- Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Zaiyuan Ye
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
| | - Guoqing Wu
- Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
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Nagashima Y, Yoshino S, Yamamoto S, Maeda N, Azumi T, Komoike Y, Okuno K, Iwasa T, Tsurutani J, Nakagawa K, Masaaki O, Hiroaki N. Lentinula edodes mycelia extract plus adjuvant chemotherapy for breast cancer patients: Results of a randomized study on host quality of life and immune function improvement. Mol Clin Oncol 2017; 7:359-366. [PMID: 28811898 PMCID: PMC5547768 DOI: 10.3892/mco.2017.1346] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 07/22/2017] [Indexed: 12/15/2022] Open
Abstract
Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of Lentinula edodes mycelia extract (LEM), which is an oral biological response modifier (BRM) medicine for cancer patients as such an adjuvant. A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, i.e., 5-fluorouracil (5-FU) + cyclophosphamide + epirubicin (FEC regimen), 5-FU + cyclophosphamide + doxorubicin/pirarubicin (FAC regimen), cyclophosphamide + doxorubicin/pirarubicin (AC regimen) and cyclophosphamide + epirubicin (EC regimen), were entered in the study. The patients were randomly divided into either an LEM or a placebo tablet group; the tablets were orally ingested daily over 2 courses of each therapy. In the placebo group, the total scores for QOL were lower on day 8 of the second course of chemotherapy compared with the baseline scores, whereas in the LEM group the scores had not decreased. In the placebo group, the QOL functional well-being score was lower on day 8 after both the first and second courses of chemotherapy compared with the baseline score, but it had not decreased in the LEM group. Evaluation of immunological parameters indicated that an increase in the proportion of regulatory T cells to peripheral blood CD4+ cells tended to be inhibited in the LEM group compared with the placebo group. Oral LEM that was coadministered with anthracycline-based chemotherapies was useful for maintaining patients' QOL and immune function. Thus, LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy.
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Affiliation(s)
- Yukiko Nagashima
- Department of Breast and Thyroid Surgery, Japan Community Health Care Organization (JCHO) Shimonoseki Medical Center, Shimonoseki, Yamaguchi 750-0061, Japan
| | - Shigehumi Yoshino
- Oncology Center, Yamaguchi University Hospital, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-0046, Japan
| | - Shigeru Yamamoto
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-0046, Japan
| | - Noriko Maeda
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-0046, Japan
| | - Tatsuya Azumi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-0046, Japan
| | - Yoshifumi Komoike
- Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Kiyotaka Okuno
- Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Tsutomu Iwasa
- Department of Medical Oncology, Kindai University School of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Junji Tsurutani
- Department of Medical Oncology, Kindai University School of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Kazuhiko Nakagawa
- Department of Medical Oncology, Kindai University School of Medicine, Osakasayama, Osaka 589-8511, Japan
| | - Oka Masaaki
- Yamaguchi University, Yamaguchi, Yamaguchi 753-8511, Japan
| | - Nagano Hiroaki
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-0046, Japan
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Metronomic chemotherapy and immunotherapy in cancer treatment. Cancer Lett 2017; 400:282-292. [PMID: 28189534 DOI: 10.1016/j.canlet.2017.01.040] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 01/26/2017] [Accepted: 01/26/2017] [Indexed: 12/14/2022]
Abstract
Systemic chemotherapy given at maximum tolerated doses (MTD) has been the mainstay of cancer treatment for more than half a century. In some chemosensitive diseases such as hematologic malignancies and solid tumors, MTD has led to complete remission and even cure. The combination of maintenance therapy and standard MTD also can generate good disease control; however, resistance to chemotherapy and disease metastasis still remain major obstacles to successful cancer treatment in the majority of advanced tumors. Metronomic chemotherapy, defined as frequent administration of chemotherapeutic agents at a non-toxic dose without extended rest periods, was originally designed to overcome drug resistance by shifting the therapeutic target from tumor cells to tumor endothelial cells. Metronomic chemotherapy also exerts anti-tumor effects on the immune system (immunomodulation) and tumor cells. The goal of immunotherapy is to enhance host anti-tumor immunities. Adding immunomodulators such as metronomic chemotherapy to immunotherapy can improve the clinical outcomes in a synergistic manner. Here, we review the anti-tumor mechanisms of metronomic chemotherapy and the preliminary research addressing the combination of immunotherapy and metronomic chemotherapy for cancer treatment in animal models and in clinical setting.
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Nelson DJ, Clark B, Munyard K, Williams V, Groth D, Gill J, Preston H, Chan A. A review of the importance of immune responses in luminal B breast cancer. Oncoimmunology 2017; 6:e1282590. [PMID: 28405507 DOI: 10.1080/2162402x.2017.1282590] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 01/10/2017] [Accepted: 01/10/2017] [Indexed: 12/14/2022] Open
Abstract
Historically, the immune environment was not considered an important target for breast cancer treatment. However, the association of lymphocytic infiltrates in triple negative and HER-2 over-amplified breast cancer subtypes with better outcomes, has provoked interest in evaluating the role of the immune system in the luminal B subtype that accounts for 39% of breast cancers and has a poor patient prognosis. It is unknown which immunosuppressive cell types or molecules (e.g., checkpoint molecules) are relevant, or where measurement is most informative. We hypothesize that a profound immunosuppressive tumor and/or lymph node milieu is prognostic and impacts on responses to therapies.
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Affiliation(s)
- Delia J Nelson
- School of Biomedical Sciences, Curtin University, Bentley, Perth, WA, Australia; CHIRI Biosciences, Curtin University, Perth, WA, Australia
| | - Briony Clark
- School of Biomedical Sciences, Curtin University, Bentley, Perth, WA, Australia; CHIRI Biosciences, Curtin University, Perth, WA, Australia
| | - Kylie Munyard
- School of Biomedical Sciences, Curtin University, Bentley, Perth, WA, Australia; CHIRI Biosciences, Curtin University, Perth, WA, Australia
| | - Vincent Williams
- School of Biomedical Sciences, Curtin University , Bentley, Perth, WA, Australia
| | - David Groth
- School of Biomedical Sciences, Curtin University, Bentley, Perth, WA, Australia; CHIRI Biosciences, Curtin University, Perth, WA, Australia
| | - Jespal Gill
- Western Diagnostics Pathology , Myaree, Perth, WA, Australia
| | - Henry Preston
- Western Diagnostics Pathology , Myaree, Perth, WA, Australia
| | - Arlene Chan
- Breast Cancer Research Centre-WA, Hollywood Private Hospital, Nedlands, WA, Australia; Curtin Medical School, Curtin University, Perth, WA, Australia
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Abstract
FOXP3-expressing regulatory T (Treg) cells, which suppress aberrant immune response against self-antigens, also suppress anti-tumor immune response. Infiltration of a large number of Treg cells into tumor tissues is often associated with poor prognosis. There is accumulating evidence that the removal of Treg cells is able to evoke and enhance anti-tumor immune response. However, systemic depletion of Treg cells may concurrently elicit deleterious autoimmunity. One strategy for evoking effective tumor immunity without autoimmunity is to specifically target terminally differentiated effector Treg cells rather than all FOXP3+ T cells, because effector Treg cells are the predominant cell type in tumor tissues. Various cell surface molecules, including chemokine receptors such as CCR4, that are specifically expressed by effector Treg cells can be the candidates for depleting effector Treg cells by specific cell-depleting monoclonal antibodies. In addition, other immunological characteristics of effector Treg cells, such as their high expression of CTLA-4, active proliferation, and apoptosis-prone tendency, can be exploited to control specifically their functions. For example, anti-CTLA-4 antibody may kill effector Treg cells or attenuate their suppressive activity. It is hoped that combination of Treg-cell targeting (e.g., by reducing Treg cells or attenuating their suppressive activity in tumor tissues) with the activation of tumor-specific effector T cells (e.g., by cancer vaccine or immune checkpoint blockade) will make the current cancer immunotherapy more effective.
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Affiliation(s)
- Atsushi Tanaka
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan.,Department of Frontier Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita 565-0871, Japan
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Roussey JA, Olszewski MA, Osterholzer JJ. Immunoregulation in Fungal Diseases. Microorganisms 2016; 4:microorganisms4040047. [PMID: 27973396 PMCID: PMC5192530 DOI: 10.3390/microorganisms4040047] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 12/02/2016] [Accepted: 12/06/2016] [Indexed: 02/07/2023] Open
Abstract
This review addresses specific regulatory mechanisms involved in the host immune response to fungal organisms. We focus on key cells and regulatory pathways involved in these responses, including a brief overview of their broader function preceding a discussion of their specific relevance to fungal disease. Important cell types discussed include dendritic cells and regulatory T cells, with a focus on specific studies relating to their effects on immune responses to fungi. We highlight the interleukin-10, programmed cell death 1, and cytotoxic T lymphocyte-associated protein 4 signaling pathways and emphasize interrelationships between these pathways and the regulatory functions of dendritic cells and regulatory T cells. Throughout our discussion, we identify selected studies best illustrating the role of these cells and pathways in response to specific fungal pathogens to provide a contextual understanding of the tightly-controlled network of regulatory mechanisms critical to determining the outcome of exposure to fungal pathogens. Lastly, we discuss two unique phenomena relating to immunoregulation, protective tolerance and immune reactivation inflammatory syndrome. These two clinically-relevant conditions provide perspective as to the range of immunoregulatory mechanisms active in response to fungi.
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Affiliation(s)
- Jonathan A Roussey
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
- Pulmonary Section, Medical Service, VA Ann Arbor Health System, Ann Arbor, MI 48105, USA.
| | - Michal A Olszewski
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
- Pulmonary Section, Medical Service, VA Ann Arbor Health System, Ann Arbor, MI 48105, USA.
- Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
| | - John J Osterholzer
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109, USA.
- Pulmonary Section, Medical Service, VA Ann Arbor Health System, Ann Arbor, MI 48105, USA.
- Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109, USA.
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