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Zhao Z, Qiu S, Zhang X, Liu S, Wang L, Guan H, He J, Hu Y, Li X, Luo S, Chen Z, Mo T, Zhang Y, Zhao X, Pan Y, Ding H, Cao J, Pan J. Characterization of a novel cell line established from mice gastrointestinal stromal model by chemical induction. Transl Oncol 2025; 56:102388. [PMID: 40233502 PMCID: PMC12022689 DOI: 10.1016/j.tranon.2025.102388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/03/2025] [Accepted: 04/05/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are a type of tumor that originates from gastrointestinal mesenchymal tissue. Although several somatic or germline mutation GIST mice were established, however, there is still a lack of an authentic mice GIST cell lines for further experimental study. METHODS We developed a chemically induced C57BL/6 J GIST model using 3- methylcholanthrene. Tumor characteristics were confirmed through histology and IHC. Primary cells were isolated to establish the mGSTc01 cell line, and molecular profiling was conducted. Additionally, we established GIST model in immunocompetent mice to evaluate their sensitivity to imatinib. RESULTS Our study successfully developed a chemically induced murine GIST model, characterized by positive staining of c-kit and DOG-1. The mGSTc01 monoclonal cell line exhibited slender morphology and expressed the c-kit marker, Whole exome sequencing uncovered mutations of Lamb1, MMP9, and c-kit in GIST cells and provided a detailed picture of the entire genome's copy number variations. RNA sequencing indicated genes associated with cell adhesion and focal adhesion were enriched in mGSTc01 cells. The mGSTc01 cells demonstrated obvious malignant behaviors, notably elevated migration, adhesion, and proliferation. In immunocompetent mice, subcutaneous xenografts not only reserved the aggressive phenotype but also displayed a response to imatinib, underscoring the model's applicability for advancing therapeutic research. CONCLUSION We firstly established a mGSTc01 cell line derived from C57BL/6 J mice GIST tumor offers, which closely mimicking human disease characteristics. It is a potent platform for investigating tumor microenvironment of GIST in mice model, and provides a novel way for new therapeutic discoveries in GIST.
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Affiliation(s)
- Zhan Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Shenghui Qiu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, PR China
| | - Xiangwei Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Shijin Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Lu Wang
- Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, 510632, PR China
| | - Hanyang Guan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Jiashuai He
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yangzhi Hu
- The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, PR China
| | - Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
| | - Simin Luo
- Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, China
| | - Zuyang Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Tianmu Mo
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Xiaoxu Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China.
| | - Jie Cao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, PR China.
| | - Jinghua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China.
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Yang P, Yu Q. Immune-related genes for the prediction of response to imatinib therapy in chronic myeloid leukemia. Carcinogenesis 2025; 46:bgae080. [PMID: 39714081 DOI: 10.1093/carcin/bgae080] [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: 09/10/2024] [Revised: 11/03/2024] [Accepted: 12/21/2024] [Indexed: 12/24/2024] Open
Abstract
Chronic myeloid leukemia (CML) is a malignant hyperplastic tumor that originates from pluripotent hematopoietic stem cells in the bone marrow. The introduction of tyrosine kinase inhibitors has significantly improved the survival rates of CML patients. This study aimed to identify immune-related genes associated with the response to imatinib (IM) therapy in CML. Gene expression profiles from IM-treated CML patients were obtained from the Gene Expression Omnibus database and categorized into high- and low-score groups based on immune scores calculated using the ESTIMATE algorithm. Subsequent bioinformatics analysis identified 428 differentially expressed immune-related genes in the CML context. Functional enrichment analysis revealed that these genes were involved in immune-related pathways, including T-cell receptor signaling and cytokine-cytokine receptor interaction. Finally, based on five modules in weighted gene co-expression network analysis and the top-ranked degree, 10 hub genes were identified. Receiver operating characteristic analysis in two Gene Expression Omnibus datasets identified IL10RA, SCN9A, and SLC26A11 as potential biomarkers for predicting IM response. We further validated these biomarkers in an independent clinical cohort of 60 CML patients treated with IM. Results from quantitative real-time polymerase chain reaction (qRT-PCR) revealed high expression of IL10RA and SLC26A11 in responders, while SCN9A showed low expression. All three genes had an area under the curve greater than 0.75, confirming their potential as predictive biomarkers. These findings deepen our understanding of functional characteristics and immune-related molecular mechanisms underlying IM response and offer promising predictive biomarkers.
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MESH Headings
- Humans
- Imatinib Mesylate/therapeutic use
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Biomarkers, Tumor/genetics
- Female
- Male
- Prognosis
- Gene Expression Profiling
- Middle Aged
- Antineoplastic Agents/therapeutic use
- Gene Regulatory Networks
- Adult
- Protein Kinase Inhibitors/therapeutic use
- Gene Expression Regulation, Leukemic/drug effects
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Affiliation(s)
- Pu Yang
- Department of Neurology, The Third Xiangya Hospital of Central South University, No. 138 Tongzipo Road, Changsha, Hunan 410013, People's Republic of China
| | - Qian Yu
- Division of Hematology, Second Xiangya Hospital, Central South University, No. 139th Renmin Middle Road, Changsha, Hunan 410011, People's Republic of China
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3
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Liu Y, Xu L, Dou Y, He Y. AXL: shapers of tumor progression and immunosuppressive microenvironments. Mol Cancer 2025; 24:11. [PMID: 39799359 PMCID: PMC11724481 DOI: 10.1186/s12943-024-02210-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 12/24/2024] [Indexed: 01/15/2025] Open
Abstract
As research progresses, our understanding of the tumor microenvironment (TME) has undergone profound changes. The TME evolves with the developmental stages of cancer and the implementation of therapeutic interventions, transitioning from an immune-promoting to an immunosuppressive microenvironment. Consequently, we focus intently on the significant role of the TME in tumor proliferation, metastasis, and the development of drug resistance. AXL is highly associated with tumor progression; however, previous studies on AXL have been limited to its impact on the biological behavior of cancer cells. An increasing body of research now demonstrates that AXL can influence the function and differentiation of immune cells, mediating immune suppression and thereby fostering tumor growth. A comprehensive analysis to identify and overcome the causes of immunosuppressive microenvironments represents a novel approach to conquering cancer. In this review, we focus on elucidating the role of AXL within the immunosuppressive microenvironments, discussing and analyzing the effects of AXL on tumor cells, T cells, macrophages, natural killer (NK) cells, fibroblasts, and other immune-stromal cells. We aim to clarify the contributions of AXL to the progression and drug resistance of cancer from its functional role in the immune microenvironment.
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Affiliation(s)
- Yihui Liu
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Lei Xu
- Department of Otolaryngology, Southwest Hospital, Army Medical University, Chongqing, 400000, China
| | - Yuanyao Dou
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China
| | - Yong He
- Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, 400042, China.
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4
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He B, Dymond L, Wood KH, Bastow ER, Satiaputra J, Li J, Johansson-Percival A, Hamzah J, Kumarasinghe MP, Ballal M, Foo J, Johansson M, Ee HC, White SW, Winteringham L, Ganss R. Immune priming and induction of tertiary lymphoid structures in a cord-blood humanized mouse model of gastrointestinal stromal tumor. Oncoimmunology 2024; 13:2406576. [PMID: 39314905 PMCID: PMC11418220 DOI: 10.1080/2162402x.2024.2406576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/16/2024] [Accepted: 09/16/2024] [Indexed: 09/25/2024] Open
Abstract
Gastrointestinal stromal tumors (GISTs) harbor diverse immune cell populations but so far immunotherapy in patients has been disappointing. Here, we established cord blood humanized mouse models of localized and disseminated GIST to explore the remodeling of the tumor environment for improved immunotherapy. Specifically, we assessed the ability of a cancer vascular targeting peptide (VTP) to bind to mouse and patient GIST angiogenic blood vessels and deliver the TNF superfamily member LIGHT (TNFS14) into tumors. LIGHT-VTP treatment of GIST in humanized mice improved vascular function and tumor oxygenation, which correlated with an overall increase in intratumoral human effector T cells. Concomitant with LIGHT-mediated vascular remodeling, we observed intratumoral high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), which resemble spontaneous TLS found in GIST patients. Thus, by overcoming the limitations of immunodeficient xenograft models, we demonstrate the therapeutic feasibility of vascular targeting and immune priming in human GIST. Since TLS positively correlate with patient prognosis and improved response to immune checkpoint inhibition, vascular LIGHT targeting in GIST is a highly translatable approach to improve immunotherapeutic outcomes.
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Affiliation(s)
- Bo He
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Larissa Dymond
- Translational Cancer Research Program, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Kira H. Wood
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Edward R. Bastow
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Jiulia Satiaputra
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Ji Li
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Anna Johansson-Percival
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Juliana Hamzah
- Imaging & Therapy Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | | | - Mohammed Ballal
- Department of General Surgery, Fiona Stanley Hospital, WesternAustralia, Australia
- Division of Surgery, School of Medicine, University of Western Australia, WesternAustralia, Australia
| | - Jonathan Foo
- Division of Surgery, School of Medicine, University of Western Australia, WesternAustralia, Australia
- Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, WesternAustralia, Australia
| | - Mikael Johansson
- Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, WesternAustralia, Australia
| | - Hooi C. Ee
- Sir Charles Gairdner Hospital, QEII Medical Centre, Perth, WesternAustralia, Australia
- Division of Internal Medicine, School of Medicine, University of Western Australia, WesternAustralia, Australia
| | - Scott W. White
- Division of Obstetrics and Gynaecology, Faculty of Medicine, Dentistry, and Health Sciences, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Louise Winteringham
- Translational Cancer Research Program, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
| | - Ruth Ganss
- Cancer Microenvironment Laboratory, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
- Translational Cancer Research Program, Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Perth, WesternAustralia, Australia
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Wang XK, Yang X, Yao TH, Tao PX, Jia GJ, Sun DX, Yi L, Gu YH. Advances in immunotherapy of M2 macrophages and gastrointestinal stromal tumor. World J Gastrointest Oncol 2024; 16:2915-2924. [PMID: 39072184 PMCID: PMC11271800 DOI: 10.4251/wjgo.v16.i7.2915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/16/2024] [Accepted: 05/28/2024] [Indexed: 07/12/2024] Open
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal-derived tumors of the GI tract. They can occur throughout the GI tract, and the survival time of some patients can be improved by first-line targeted therapy with imatinib. However, there are some limitations with imatinib treatment. Immunotherapy for GIST has attracted much attention in recent years, and as one of the most abundant cells in the GIST microenvironment, M2 macrophages play an important role in disease progression. They have unique anti-inflammatory and pro-tumorigenic effects and are one target for immunotherapy. This review summarizes the connection between different factors and the programmed death receptor-1/programmed death ligand-1 pathway and M2 macrophages to reactivate or enhance anti-tumor immunity and improve imatinib efficacy, and to provide new ideas for GIST immunotherapy.
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Affiliation(s)
- Xiao-Ke Wang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Xin Yang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Tong-Han Yao
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Peng-Xian Tao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Guan-Jun Jia
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - De-Xian Sun
- Graduate School, Qinghai University, Xining 810016, Qinghai Province, China
| | - Lin Yi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yuan-Hui Gu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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6
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Yu G, Liu R, Li J, Zhao G, Wang Y. The immunotherapy in gastrointestinal stromal tumors. Heliyon 2024; 10:e33617. [PMID: 39040340 PMCID: PMC11260923 DOI: 10.1016/j.heliyon.2024.e33617] [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: 01/03/2024] [Revised: 06/21/2024] [Accepted: 06/24/2024] [Indexed: 07/24/2024] Open
Abstract
Using Tyrosine Kinase Inhibitors (TKIs) for gastrointestinal stromal tumors (GIST) has significantly reduced the risk of recurrence and prolonged survival. Immunotherapy has demonstrated efficacy in multiple solid tumors, but its effectiveness in GIST remains uncertain. Although early clinical studies indicate good tolerability of immunotherapy in patients, the efficacy is not as desired. Therefore, identifying the subset of GIST patients who benefit from immunotherapy and coordinating the relationship between immunotherapy and TKI treatment are crucial issues to be explored. In this review, we aims to provide a retrospective analysis of relevant literature and find that GIST patients exhibit a rich presence of tumor-infiltrating immune cells, which play critical roles in the immune surveillance and evasion processes of tumors. This review incorporates a selection of 48 articles published between 2002 and 2023, sourced from PubMed, EBSCO, and Google Scholar databases.
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Affiliation(s)
- Guilin Yu
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Ruibin Liu
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
- Department of Clinical Integration of Traditional Chinese and Western Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Jiayao Li
- Liaoning Normal University Haihua College,Liaoning, China
| | - Guohua Zhao
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yue Wang
- Department of General Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
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7
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Yu Y, Yu M, Luo L, Zhang Z, Zeng H, Chen Y, Lin Z, Chen M, Wang W. Molecular characteristics and immune microenvironment of gastrointestinal stromal tumours: targets for therapeutic strategies. Front Oncol 2024; 14:1405727. [PMID: 39070147 PMCID: PMC11272528 DOI: 10.3389/fonc.2024.1405727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 06/24/2024] [Indexed: 07/30/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours, arising mainly from the interstitial cells of Cajal (ICCs) of the gastrointestinal tract. As radiotherapy and chemotherapy are generally ineffective for GISTs, the current primary treatment is surgical resection. However, surgical resection is not choice for most patients. Therefore, new therapeutic strategies are urgently needed. Targeted therapy, represented by tyrosine kinase inhibitors (TKIs), and immunotherapy, represented by immune checkpoint inhibitor therapies and chimeric antigen receptor T-cell immunotherapy (CAR-T), offer new therapeutic options in GISTs and have shown promising treatment responses. In this review, we summarize the molecular classification and immune microenvironment of GISTs and discuss the corresponding targeted therapy and immunotherapy options. This updated knowledge may provide more options for future therapeutic strategies and applications in GISTs.
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Affiliation(s)
- Yang Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengdie Yu
- Guangzhou KingMed Diagnostics Group Co., Ltd., Guangzhou, Guangdong, China
| | - Lijie Luo
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Zijing Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Haiping Zeng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Yan Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Zeyu Lin
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Mengnan Chen
- Department of Thyroid and Breast Surgery, Baiyun Hospital, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine, Guangzhou, Guangdong, China
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Kim HD, Ryu MH, Park YS, Yoo C, Kim SJ, Kang YK. Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 Plus Imatinib for Advanced Treatment-Refractory Gastrointestinal Stromal Tumors. Clin Cancer Res 2024; 30:2743-2750. [PMID: 38662455 DOI: 10.1158/1078-0432.ccr-23-4065] [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: 12/27/2023] [Revised: 02/16/2024] [Accepted: 04/22/2024] [Indexed: 07/02/2024]
Abstract
PURPOSE In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). PATIENTS AND METHODS Patients with advanced GIST whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3 + 3 dose escalation scheme was applied. Intravenous administration of PDR001 at 400 mg for every 4 weeks plus imatinib (300 and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate at 12 weeks. Exploratory biomarker analysis was performed based on PDL1 IHC, next-generation sequencing, and multiplexed IHC. RESULTS No dose-limiting toxicity was observed in the phase Ib part (n = 10), and dose level II was selected as the recommended phase II dose. In the phase II part (n = 29), there was no objective response, and the disease control rate at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n = 36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3 to 4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T-cell density was associated with a favorable PFS but to a limited degree. Tumor mutational burden and PDL1 were not associated with better PFS. CONCLUSIONS In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.
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Affiliation(s)
- Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Joo Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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9
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Chaffey LE, Roberti A, Bowman A, O'Brien CJ, Som L, Purvis GS, Greaves DR. Drug repurposing screen identifies novel anti-inflammatory activity of sunitinib in macrophages. Eur J Pharmacol 2024; 969:176437. [PMID: 38417608 DOI: 10.1016/j.ejphar.2024.176437] [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: 09/22/2023] [Revised: 01/29/2024] [Accepted: 02/16/2024] [Indexed: 03/01/2024]
Abstract
Inflammation is a driver of human disease and an unmet clinical need exists for new anti-inflammatory medicines. As a key cell type in both acute and chronic inflammatory pathologies, macrophages are an appealing therapeutic target for anti-inflammatory medicines. Drug repurposing - the use of existing medicines for novel indications - is an attractive strategy for the identification of new anti-inflammatory medicines with reduced development costs and lower failure rates than de novo drug discovery. In this study, FDA-approved medicines were screened in a murine macrophage NF-κB reporter cell line to identify potential anti-inflammatory drug repurposing candidates. The multi-tyrosine kinase inhibitor sunitinib was found to be a potent inhibitor of NF-κB activity and suppressor of inflammatory mediator production in murine bone marrow derived macrophages. Furthermore, oral treatment with sunitinib in mice was found to reduce TNFα production, inflammatory gene expression and organ damage in a model of endotoxemia via inhibition of NF-κB. Finally, we revealed sunitinib to have immunomodulatory effects in a model of chronic cardiovascular inflammation by reducing circulating TNFα. This study validates drug repurposing as a strategy for the identification of novel anti-inflammatory medicines and highlights sunitinib as a potential drug repurposing candidate for inflammatory disease via inhibition of NF-κB signalling.
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Affiliation(s)
- Laura E Chaffey
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - Annabell Roberti
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - Amelia Bowman
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - Conan Jo O'Brien
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - Liliana Som
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - Gareth Sd Purvis
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom
| | - David R Greaves
- Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxfordshire, OX1 3RE, United Kingdom.
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10
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Wang S, Wang H, Li C, Liu B, He S, Tu C. Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications. MedComm (Beijing) 2024; 5:e489. [PMID: 38469550 PMCID: PMC10925885 DOI: 10.1002/mco2.489] [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: 06/25/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 03/13/2024] Open
Abstract
Cancer is a major cause of death globally, and traditional treatments often have limited efficacy and adverse effects. Immunotherapy has shown promise in various malignancies but is less effective in tumors with low immunogenicity or immunosuppressive microenvironment, especially sarcomas. Tertiary lymphoid structures (TLSs) have been associated with a favorable response to immunotherapy and improved survival in cancer patients. However, the immunological mechanisms and clinical significance of TLS in malignant tumors are not fully understood. In this review, we elucidate the composition, neogenesis, and immune characteristics of TLS in tumors, as well as the inflammatory response in cancer development. An in-depth discussion of the unique immune characteristics of TLSs in lung cancer, breast cancer, melanoma, and soft tissue sarcomas will be presented. Additionally, the therapeutic implications of TLS, including its role as a marker of therapeutic response and prognosis, and strategies to promote TLS formation and maturation will be explored. Overall, we aim to provide a comprehensive understanding of the role of TLS in the tumor immune microenvironment and suggest potential interventions for cancer treatment.
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Affiliation(s)
- Siyu Wang
- Department of OrthopaedicsThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Xiangya School of MedicineCentral South UniversityChangshaHunanChina
| | - Hua Wang
- Department of OrthopaedicsThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Chenbei Li
- Department of OrthopaedicsThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Binfeng Liu
- Department of OrthopaedicsThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Shasha He
- Department of OncologyThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
| | - Chao Tu
- Department of OrthopaedicsThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Hunan Key Laboratory of Tumor Models and Individualized MedicineThe Second Xiangya Hospital of Central South UniversityChangshaHunanChina
- Shenzhen Research Institute of Central South UniversityGuangdongChina
- Changsha Medical UniversityChangshaChina
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11
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Guo X, Li Y, Wan B, Lv Y, Wang X, Liu G, Wang P. ETV1 inhibition depressed M2 polarization of tumor-associated macrophage and cell process in gastrointestinal stromal tumor via down-regulating PDE3A. J Clin Biochem Nutr 2023; 72:139-146. [PMID: 36936869 PMCID: PMC10017324 DOI: 10.3164/jcbn.22-47] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 07/13/2022] [Indexed: 01/15/2023] Open
Abstract
M2-type polarization of tumor associated-macrophage (TAM) is involved in the malignancy of gastrointestinal stromal tumor (GIST) progression. ETS variant 1 (ETV1) has been previously validated to regulate GIST pathogenesis. Our study intended to explore the role and mechanism of ETV1 in mediating the M2-polarization of TAM in GIST progression. First, we analyzed the correlation between ETV1 expression and M2-polarization in GIST tissues. IL-4 was used to treat THP-1-derived TAM cells and IL-4-stimulated TAM were co-cultured with GIST-T1 cells to mimic the GIST microenvironment. A loss-of-function assay was performed to explore the role of ETV1. Results showed that ETV1 elevation was positively correlated with M2-polarization. IL-4-induced TAM promoted ETV1 expression, silencing ETV1 inhibited proliferation, invasion and KIT activation in IL-4-treated GIST cells, while cell apoptosis was enhanced. Besides, co-culture of ETV1-silenced GIST cells significantly depressed M2-polarization in TAM, presented as decreased levels of CD206, Agr-1 and cytokines, as well as the proportion of CD206-positive TAM. PDE3A was positively correlated with ETV1 and M2-polarization. Overexpressing PDE3A reversed the inhibitory effects of ETV1 silencing. Generally, ETV1 inhibition depressed M2-polarization of TAM in GIST and its promotion on pathological aggravation via down-regulating PDE3A. This evidence may provide a new target for GIST regulation.
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Affiliation(s)
- Xueyan Guo
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Yulong Li
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Bingbing Wan
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Yifei Lv
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Xue Wang
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Guisheng Liu
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
| | - Ping Wang
- Department of Gastroenterology, Shaanxi Provincial People’s Hospital, Xi’an, Shaanxi 710068, China
- To whom correspondence should be addressed. E-mail:
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12
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Cai H, Chen Y, Chen X, Sun W, Li Y. Tumor-associated macrophages mediate gastrointestinal stromal tumor cell metastasis through CXCL2/CXCR2. Cell Immunol 2023; 384:104642. [PMID: 36577281 DOI: 10.1016/j.cellimm.2022.104642] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 10/26/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are linked with the progression and poor prognosis of multifarious solid tumors, but the regulatory mechanisms involved in gastrointestinal stromal tumors (GIST) remain indistinct. This study intended to delve into the job of TAM-derived chemokines in promoting metastasis in GIST microenvironment. METHODS Expression levels of M2-TAM markers and CXCL2 in primary and metastatic tissues of GIST were analyzed by bioinformatics methods, and we analyzed the correlation between CXCL2 and M2-TAM markers. Immunofluorescence was applied to assay CXCL2 and M2-TAM marker protein (CD68 and CD206) expression in tumor tissues. Serum CXCL2 concentration in metastatic and non-metastatic patients was assayed by ELISA. The differentiation of THP-1 cells was tested by flow cytometry. Cell function test was utilized to analyze the viability, invasion and migration of GIST cells. Western blot was used to examine the expression of epithelial-mesenchymal transition (EMT)-related proteins. The mouse liver metastasis model was established, and the effects of CXCL2 and EMT-related genes on metastasis were confirmed by hematoxylin-eosin staining and immunohistochemistry experiments. RESULTS Bioinformatics analysis ascertained that M2-TAM marker proteins and chemokine CXCL2 were highly expressed in GIST metastatic tissues, and CXCL2 and TAM were co-located in tumor tissues. Results of in vitro cell function experiments displayed that CXCL2 secreted by M2-TAM promoted the invasion, migration and EMT of GIST tumor cells, and the anti-CXCL2 antibody could block the metastasis promoting effect of CXCL2. Additionally, the silencing of CXCR2 in GIST cells inhibited the metastasis promoting effect of CXCL2. Animal studies further confirmed that CXCL2 promoted liver metastasis of GIST in vivo. CONCLUSION This study preliminarily revealed the mechanism of M2-TAM promoting tumor metastasis by secreting CXCL2 in GIST tumor microenvironment, and proffered theoretical reference for the development of immunotherapy strategies targeting M2-TAM.
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Affiliation(s)
- Hongke Cai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yi Chen
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Xi Chen
- Department of Pathology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Weiping Sun
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Yang Li
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
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13
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Shi T, Sun M, Lu C, Meng F. Self-assembled nanoparticles: A new platform for revolutionizing therapeutic cancer vaccines. Front Immunol 2023; 14:1125253. [PMID: 36895553 PMCID: PMC9988954 DOI: 10.3389/fimmu.2023.1125253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/07/2023] [Indexed: 02/23/2023] Open
Abstract
Cancer vaccines have had some success in the past decade. Based on in-depth analysis of tumor antigen genomics, many therapeutic vaccines have already entered clinical trials for multiple cancers, including melanoma, lung cancer, and head and neck squamous cell carcinoma, which have demonstrated impressive tumor immunogenicity and antitumor activity. Recently, vaccines based on self-assembled nanoparticles are being actively developed as cancer treatment, and their feasibility has been confirmed in both mice and humans. In this review, we summarize recent therapeutic cancer vaccines based on self-assembled nanoparticles. We describe the basic ingredients for self-assembled nanoparticles, and how they enhance vaccine immunogenicity. We also discuss the novel design method for self-assembled nanoparticles that pose as a promising delivery platform for cancer vaccines, and the potential in combination with multiple therapeutic approaches.
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Affiliation(s)
- Tianyu Shi
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Mengna Sun
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Changchang Lu
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Fanyan Meng
- The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.,The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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14
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The Prognostic Value of Plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) in Patients with Gastrointestinal Stromal Tumor. Cancers (Basel) 2022; 14:cancers14235753. [PMID: 36497235 PMCID: PMC9737373 DOI: 10.3390/cancers14235753] [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: 10/20/2022] [Revised: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND This study investigates the prognostic value of plasma Programmed Death Protein-1 (PD-1) and Programmed Death-Ligand 1 (PD-L1) concentrations in patients with Gastrointestinal Stromal Tumor (GIST). METHODS Patients with GIST were included (n = 157) from the two Danish sarcoma centers, independent of disease- and treatment status. The patients were divided into three subgroups; 1: patients with localized disease who underwent radical surgery; 2: patients with local, locally advanced, or metastatic disease; and 3: patients without measurable disease who had undergone radical surgery. Sensitive electrochemiluminescence immune-assays were used to determine PD-1 and PD-L1 concentration in plasma samples. The primary endpoint was the PFS. RESULTS No patients progressed in group 1 (n = 15), 34 progressed in group 2 (n = 122), and three progressed in group 3 (n = 20). Significantly higher plasma concentrations of PD-1 (p = 0.0023) and PD-L1 (0.012) were found in patients in group 2 compared to PD-1/PD-L1 levels in postoperative plasma samples from patient group 1. Patients with active GIST having a plasma concentration of PD-L1 above the cutoff (225 pg/mL) had a significantly poorer prognosis compared to patients with plasma PD-L1 concentration below the cutoff. CONCLUSIONS Plasma PD-L1 shows potential as a prognostic biomarker in patients with GIST and should be further evaluated.
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15
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Shen C, Han L, Liu B, Zhang G, Cai Z, Yin X, Yin Y, Chen Z, Zhang B. The KDM6A-SPARCL1 axis blocks metastasis and regulates the tumour microenvironment of gastrointestinal stromal tumours by inhibiting the nuclear translocation of p65. Br J Cancer 2022; 126:1457-1469. [PMID: 35136209 PMCID: PMC9090789 DOI: 10.1038/s41416-022-01728-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 01/07/2022] [Accepted: 01/28/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND It is urgent to explore the pathogenic mechanism of gastrointestinal stromal tumours (GISTs). KDM6A, a histone demethylase, can activate gene transcription and has not been reported in GISTs. SPARCL1 may serve as a metastasis marker in GIST, but the molecular mechanism remains to be further explored. This study aimed to explore the biological function and molecular mechanism of KDM6A and SPARCL1 in GIST. METHODS CCK-8, live cell count, colony formation, wound-healing and Transwell migration and invasion assays were employed to detect the cell proliferation, migration and invasion. A xenograft model and hepatic metastasis model were used to assess the role of KDM6A and SPARCL1 in vivo. RESULTS KDM6A inhibited the proliferation, migration and invasion of GIST cells. Mechanistically, KDM6A promotes the transcription of SPARCL1 by demethylating histone H3 lysine trimethylation and consequently leads to the inactivation of p65. SPARCL1 affected the metastasis of GIST cells in a mesenchymal-epithelial transition- and matrix-metalloproteinase-dependent manner. SPARCL1 knockdown promoted angiogenesis, M2 polarisation and macrophage recruitment by inhibiting the phosphorylation of p65. Moreover, KDM6A and SPARCL1 inhibited hepatic metastasis and macrophage infiltration in vivo. CONCLUSIONS Our findings establish the critical role of the KDM6A-SPARCL1-p65 axis in restraining the malignancy of GIST.
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Affiliation(s)
- Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Luyin Han
- Intensive care unit, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Baike Liu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Guixiang Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Zhaolun Cai
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Xiaonan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Yuan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Zhixin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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16
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Lu Y, Zhang J, Chen Y, Kang Y, Liao Z, He Y, Zhang C. Novel Immunotherapies for Osteosarcoma. Front Oncol 2022; 12:830546. [PMID: 35433427 PMCID: PMC9012135 DOI: 10.3389/fonc.2022.830546] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/28/2022] [Indexed: 02/05/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone sarcoma mainly affecting adolescents and young adults, which often progresses to pulmonary metastasis and leads to the death of OS patients. OS is characterized as a highly heterogeneous cancer type and the underlying pathologic mechanisms triggering tumor progress and metastasis are incompletely recognized. Surgery combined with neoadjuvant and postoperative chemotherapy has elevated 5-year survival to over 70% for patients with localized OS tumors, as opposed to only 20% of patients with recurrence and/or metastasis. Therefore, novel therapeutic strategies are needed to overcome the drawbacks of conventional treatments. Immunotherapy is gaining momentum for the treatment of OS with an increasing number of FDA-approved therapies for malignancies resistant to conventional therapies. Here, we review the OS tumor microenvironment and appraise the promising immunotherapies available in the management of OS.
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Affiliation(s)
- Yubao Lu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiahe Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yutong Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yuchen Kang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Zhipeng Liao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yuanqi He
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Cangyu Zhang
- Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou, China
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17
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de Nonneville A, Finetti P, Picard M, Monneur A, Pantaleo MA, Astolfi A, Ostrowski J, Birnbaum D, Mamessier E, Bertucci F. CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response. Cancers (Basel) 2022; 14:cancers14051306. [PMID: 35267618 PMCID: PMC8909029 DOI: 10.3390/cancers14051306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Gastrointestinal stromal tumors (GIST) are the most frequent sarcomas of the gastrointestinal tract. Identification of novel prognostic and/or therapeutic targets is a major issue to overcome tyrosine kinase inhibitors resistances. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including sarcomas. CSPG4 expression has never been studied in GIST. In this work we analyzed CSPG4 mRNA expression in a large series of clinical GIST samples given the scarcity of disease (n = 309 patients). We find that high CSPG4 expression is independently associated with disease-free survival, and with an immune landscape favorable to induce strong cytotoxic immune response after NK cell stimulation. Our results suggest the potential value of CSPG4-specific chimeric antigen receptor-redirected cytokine-induced killer lymphocytes treatment in GIST, notably “CSPG4-high” tumors, and calls for preclinical validation, drug testing in vivo, then in clinical trials. Abstract The treatment of gastrointestinal stromal tumors (GIST) must be improved through the development of more reliable prognostic factors and of therapies able to overcome imatinib resistance. The immune system represents an attractive tool. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in sarcomas. CSPG4 expression has never been studied in GIST. We analyzed CSPG4 mRNA expression data of 309 clinical GIST samples profiled using DNA microarrays and searched for correlations with clinicopathological and immune features. CSPG4 expression, higher in tumors than normal digestive tissues, was heterogeneous across tumors. High expression was associated with AFIP low-risk, gastric site, and localized stage, and independently with longer postoperative disease-free survival (DFS) in localized stage. The correlations between CSPG4 expression and immune signatures highlighted a higher anti-tumor immune response in “CSPG4-high” tumors, relying on both the adaptive and innate immune system, in which the boost of NK cells by CSPG4-CAR.CIKs might be instrumental, eventually combined with immune checkpoint inhibitors. In conclusion, high CSPG4 expression in GIST is associated with better DFS and offers an immune environment favorable to a vulnerability to CAR.CIKs.
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Affiliation(s)
- Alexandre de Nonneville
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
- Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, INSERM, 13009 Marseille, France;
| | - Pascal Finetti
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
| | - Maelle Picard
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
| | - Audrey Monneur
- Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, INSERM, 13009 Marseille, France;
| | - Maria Abbondanza Pantaleo
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; (M.A.P.); (A.A.)
| | - Annalisa Astolfi
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, 40138 Bologna, Italy; (M.A.P.); (A.A.)
| | - Jerzy Ostrowski
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center of Postgraduate Education, 01-813 Warsaw, Poland;
- Department of Genetics, Maria Sklodowska-Curie National Institute of Oncology, 02-781 Warsaw, Poland
| | - Daniel Birnbaum
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
| | - Emilie Mamessier
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
| | - François Bertucci
- Predictive Oncology Laboratory, Equipe Labellisée Ligue Nationale Contre Le Cancer, Centre de Recherche en Cancérologie de Marseille (CRCM), Institut Paoli-Calmettes, Inserm UMR1068, CNRS UMR7258, Aix-Marseille University, 13009 Marseille, France; (A.d.N.); (P.F.); (M.P.); (D.B.); (E.M.)
- Department of Medical Oncology, Institut Paoli-Calmettes, Aix-Marseille University, CNRS, INSERM, 13009 Marseille, France;
- Correspondence: ; Tel.: +33-4-91-22-35-37; Fax: +33-4-91-22-36-70
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Herlea V, Roșulescu A, Calotă VC, Croitoru V, Stoica Mustafa E, Vasilescu C, Alexandrescu S, Dumitrașcu T, Popescu I, Dima SO, Sajin M. Combined Positive Score for Programmed Death Ligand-1 Expression and Inflammatory Microenvironment in Gastrointestinal Stromal Tumors. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:174. [PMID: 35208498 PMCID: PMC8924898 DOI: 10.3390/medicina58020174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/17/2022] [Accepted: 01/21/2022] [Indexed: 11/16/2022]
Abstract
Background and Objectives: GISTs are the most frequent type of mesenchymal neoplasm of the digestive tract. The prognosis is mainly determined by tumor dimensions, mitotic rate and location, but other less well-documented factors can influence evolution and survival. The immune microenvironment and checkpoint molecule expression were proven to impact the prognosis in different types of cancer. The aim of this study was to determine PD-L1 expression in GISTs and to evaluate the level of intratumoral immune infiltration in relation to prognostic variables and survival. Materials and Methods: Sixty-five GISTs diagnosed in the same institution between 2015 and 2018 were immunohistochemically tested for PD-L1 and evaluated using CPS. Immune cells were emphasized, with CD3, CD4, CD8, CD20 and CD68 antibodies and quantified. All data were processed using statistical tools. Results: The median age was 61 years (range, 28-78) and 36 patients (55.4%) were males. The location of the tumors was predominantly gastric (46%), followed by the small bowel (17%) and colorectal (6%). In addition, 11% were EGISTs and 20% were secondary tumors (11% metastases and 9% local recurrences). PD-L1 had a variable expression in tumor and inflammatory cells, with a CPS ranging from 0 to 100. Moreover, 64.6% of cases were PD-L1 positive with no significant differences among categories of variables, such as the age and the sex of the patient, tumor location, the primary or secondary character of the tumor, dimensions, mitotic rate, the risk of disease progression and tumor cell type. Immune cells had a variable distribution throughout the tumors. CD3+ lymphocytes were the most frequent type. CD20+ cells were identified in a larger number in tumors ≤5 cm (p = 0.038). PD-L1-positive tumors had a higher number of immune cells, particularly CD3+, CD20+ and CD68+, in comparison to PD-L1-negative ones (p = 0.032, p = 0.051, p = 0.008). Epithelioid and mixed cell-type tumors had a higher number of CD68+ cells. Survival was not influenced by PD-L1 expression; instead, it was decreased in multifocal tumors (p = 0.0001) and in cases with Ki67 ≥ 50% (p = 0.008). Conclusions: PD-L1-positive expression and the presence of different immune cell types, in variable quantities, can contribute to a better understanding of the complex interactions between tumor cells and the microenvironment, with a possible therapeutic role in GISTs.
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Affiliation(s)
- Vlad Herlea
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.R.); (E.S.M.)
- Faculty of Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania;
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Alexandra Roșulescu
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.R.); (E.S.M.)
- “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.V.); (S.A.); (T.D.); (M.S.)
| | | | - Vlad Croitoru
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania;
| | - Elena Stoica Mustafa
- Department of Pathology, Fundeni Clinical Institute, 022328 Bucharest, Romania; (A.R.); (E.S.M.)
| | - Cătălin Vasilescu
- “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.V.); (S.A.); (T.D.); (M.S.)
- Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Sorin Alexandrescu
- “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.V.); (S.A.); (T.D.); (M.S.)
- Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Traian Dumitrașcu
- “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.V.); (S.A.); (T.D.); (M.S.)
- Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Irinel Popescu
- Faculty of Medicine, “Titu Maiorescu” University, 031593 Bucharest, Romania;
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Center of General Surgery and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Maria Sajin
- “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania; (C.V.); (S.A.); (T.D.); (M.S.)
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Sun X, Shu P, Fang Y, Yuan W, Zhang Q, Sun J, Fu M, Xue A, Gao X, Shen K, Hou Y, Sun Y, Qin J, Qin X. Clinical and Prognostic Significance of Tumor-Infiltrating CD8+ T Cells and PD-L1 Expression in Primary Gastrointestinal Stromal Tumors. Front Oncol 2021; 11:789915. [PMID: 34956906 PMCID: PMC8709532 DOI: 10.3389/fonc.2021.789915] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/19/2021] [Indexed: 11/14/2022] Open
Abstract
Purpose Immunotherapy for gastrointestinal stromal tumors (GISTs) remains a clinical challenge. The present study aimed to explore the clinical and prognostic significance of immune cell infiltration and PD-L1 expression in GISTs. Methods A total of 507 clinical tissue specimens of primary GISTs were collected for immunohistochemical analysis of immune cell infiltration and PD-L1 expression. Influencing factors of survival were evaluated by Kaplan–Meier analysis. Univariate and multivariate analyses were performed using the Cox regression model. Results There were significant differences in sex, tumor location, size, mitotic index, NIH risk grade, and cell morphology between different gene mutation types of GISTs. Immune cell infiltration in GISTs mainly involved macrophages and T cells. PD-1 was expressed in 48.5% of the tissue specimens, and PD-L1 expression was detected in 46.0% of the samples. PD-L1 expression was negatively correlated with the tumor size and mitotic index but positively correlated with the number of CD8+ T cells. There were significant differences in the number of CD8+ T cells between different gene mutation types. Wild type-mutant GISTs were enriched with CD8+ T cells as compared with KIT- and PDGFRA-mutant GISTs. The number of CD8+ T cells was higher in non-gastric GISTs. PD-L1 and CD8+ T cells were independent predictors for better relapse-free survival of GISTs. Conclusions PD-L1 expression is a predictive biomarker for better prognosis of GISTs. Non-gastric GIST patients with wild-type mutations may be the beneficiaries of PD-1/PD-L1 inhibitors.
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Affiliation(s)
- Xiangfei Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Ping Shu
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Wei Yuan
- Department of Pathology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Qiang Zhang
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Jianyi Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Min Fu
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Anwei Xue
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Xiaodong Gao
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
- *Correspondence: Xiaodong Gao, ; Kuntang Shen,
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
- *Correspondence: Xiaodong Gao, ; Kuntang Shen,
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, Shanghai, China
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Roulleaux Dugage M, Jones RL, Trent J, Champiat S, Dumont S. Beyond the Driver Mutation: Immunotherapies in Gastrointestinal Stromal Tumors. Front Immunol 2021; 12:715727. [PMID: 34489967 PMCID: PMC8417712 DOI: 10.3389/fimmu.2021.715727] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are a subtype of soft tissue sarcoma (STS), and have become a concept of oncogenic addiction and targeted therapies.The large majority of these tumors develop after a mutation in KIT or platelet derived growth factor receptor α (PDGFRα), resulting in uncontrolled proliferation. GISTs are highly sensitive to imatinib. GISTs are immune infiltrated tumors with a predominance of tumor-associated macrophages (TAMs) and T-cells, including many CD8+ T-cells, whose numbers are prognostic. The genomic expression profile is that of an inhibited Th1 response and the presence of tertiary lymphoid structures and B cell signatures, which are known as predictive to response to ICI. However, the microtumoral environment has immunosuppressive attributes, with immunosuppressive M2 macrophages, overexpression of indoleamine 2,3-dioxygenase (IDO) or PD-L1, and loss of major histocompatibility complex type 1. In addition to inhibiting the KIT oncogene, imatinib appears to act by promoting cytotoxic T-cell activity, interacting with natural killer cells, and inhibiting the expression of PD-L1. Paradoxically, imatinib also appears to induce M2 polarization of macrophages. There have been few immunotherapy trials with anti-CTLA-4 or anti-PD-L1drugs and available clinical data are not very promising. Based on this comprehensive analysis of TME, we believe three immunotherapeutic strategies must be underlined in GIST. First, patients included in clinical trials must be better selected, based on the identified driver mutation (such as PDGFRα D842V mutation), the presence of tertiary lymphoid structures (TLS) or PD-L1 expression. Moreover, innovative immunotherapeutic agents also provide great interest in GIST, and there is a strong rationale for exploring IDO targeting after disease progression during imatinib therapy. Finally and most importantly, there is a strong rationale to combine of c-kit inhibition with immune checkpoint inhibitors.
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Affiliation(s)
| | - Robin Lewis Jones
- Division of Clinical Studies, Institute of Cancer Research & Sarcoma Unit of the Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Jonathan Trent
- Department of Medicine, Division of Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Stéphane Champiat
- Département d’Innovation Thérapeutique et des Essais Précoces (DITEP), Gustave Roussy, Université Paris Saclay, Villejuif, France
| | - Sarah Dumont
- Département d’Oncologie Médicale, Gustave Roussy, Université Paris Saclay, Villejuif, France
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21
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Sun X, Sun J, Yuan W, Gao X, Fu M, Xue A, Li H, Shu P, Fang Y, Hou Y, Shen K, Sun Y, Qin J, Qin X. Immune Cell Infiltration and the Expression of PD-1 and PD-L1 in Primary PDGFRA-Mutant Gastrointestinal Stromal Tumors. J Gastrointest Surg 2021; 25:2091-2100. [PMID: 33169322 DOI: 10.1007/s11605-020-04860-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 10/31/2020] [Indexed: 01/31/2023]
Abstract
PURPOSE To characterize the immune cell profile and expression of PD-1, PD-L1, and IDO in PDGFRA-mutant gastrointestinal stromal tumors (GISTs). METHODS The clinicopathological data of PDGFRA-mutant GIST patients who received surgical resection in Zhongshan Hospital between January 2013 and August 2019 were reviewed retrospectively. The specimens of tissue chips were detected for immune cell infiltration and the expression of PD-1, PD-L1, and IDO by immunohistochemical staining. RESULTS CD3+, CD8+, and CD68+ cells were the main infiltrating immune cells in the 42 patients included in this study. In addition, CD4+, CD56+, Foxp3+, and CD20+ cells were also observed. A higher CD8+ T cell count was associated with smaller tumor size and PDGFRA D842V mutation (P = 0.047, P = 0.005). A higher CD3+ and CD68+ cell count was associated with a higher mitotic index (P = 0.022, P = 0.006). CD4+ and CD20+ cell count was associated with tumor morphology (P = 0.002, P = 0.045). PD-1 expression was present in 37 (88%) samples. Eighteen samples were positive for PD-L1 expression, and it was higher in small vs. large tumors (P = 0.012) and epithelioid and mixed cell type vs. spindle cell type GISTs (P = 0.046). IDO expression was positive in all 42 patients. The number of CD4+ cells was significantly greater in the specimens with high IDO expression (P = 0.012). CONCLUSION There were abundant infiltrating immune cells in PDGFRA-mutant GISTs. PD-L1 expression was negatively associated with tumor size. The immunotherapy targeting PD-1/PD-L1 checkpoint and IDO may be valuable.
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Affiliation(s)
- Xiangfei Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Jianyi Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Wei Yuan
- Department of Pathology, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Xiaodong Gao
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Min Fu
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Anwei Xue
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - He Li
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Ping Shu
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China.
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China.
| | - Yihong Sun
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Jing Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
| | - Xinyu Qin
- Department of General Surgery, Zhongshan Hospital, Fudan University School of Medicine, #180 Fenglin Road, Shanghai, 200032, China
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22
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Arshad J, Costa PA, Barreto-Coelho P, Valdes BN, Trent JC. Immunotherapy Strategies for Gastrointestinal Stromal Tumor. Cancers (Basel) 2021; 13:3525. [PMID: 34298737 PMCID: PMC8306810 DOI: 10.3390/cancers13143525] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 01/13/2023] Open
Abstract
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. The management of locally advanced or metastatic unresectable GIST involves detecting KIT, PDGFR, or other molecular alterations targeted by imatinib and other tyrosine kinase inhibitors. The role of immunotherapy in soft tissue sarcomas is growing fast due to multiple clinical and pre-clinical studies with no current standard of care. The potential therapies include cytokine-based therapy, immune checkpoint inhibitors, anti-KIT monoclonal antibodies, bi-specific monoclonal antibodies, and cell-based therapies. Here we provide a comprehensive review of the immunotherapeutic strategies for GIST.
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Affiliation(s)
- Junaid Arshad
- Hematology-Oncology Department, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
| | - Philippos A. Costa
- Internal Medicine Department, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA; (P.A.C.); (P.B.-C.)
| | - Priscila Barreto-Coelho
- Internal Medicine Department, Jackson Memorial Hospital, University of Miami, Miami, FL 33136, USA; (P.A.C.); (P.B.-C.)
| | | | - Jonathan C. Trent
- Hematology-Oncology Department, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA;
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23
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Abstract
Therapeutic cancer vaccines have undergone a resurgence in the past decade. A better understanding of the breadth of tumour-associated antigens, the native immune response and development of novel technologies for antigen delivery has facilitated improved vaccine design. The goal of therapeutic cancer vaccines is to induce tumour regression, eradicate minimal residual disease, establish lasting antitumour memory and avoid non-specific or adverse reactions. However, tumour-induced immunosuppression and immunoresistance pose significant challenges to achieving this goal. In this Review, we deliberate on how to improve and expand the antigen repertoire for vaccines, consider developments in vaccine platforms and explore antigen-agnostic in situ vaccines. Furthermore, we summarize the reasons for failure of cancer vaccines in the past and provide an overview of various mechanisms of resistance posed by the tumour. Finally, we propose strategies for combining suitable vaccine platforms with novel immunomodulatory approaches and standard-of-care treatments for overcoming tumour resistance and enhancing clinical efficacy.
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Affiliation(s)
- Mansi Saxena
- Vaccine and Cell Therapy Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Hematology and Oncology Department, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sjoerd H van der Burg
- Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands
| | | | - Nina Bhardwaj
- Vaccine and Cell Therapy Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Hematology and Oncology Department, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Parker Institute of Cancer Immunotherapy, San Francisco, CA, USA.
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24
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Tolba MF, Elghazaly H, Bousoik E, Elmazar MMA, Tolaney SM. Novel combinatorial strategies for boosting the efficacy of immune checkpoint inhibitors in advanced breast cancers. Clin Transl Oncol 2021; 23:1979-1994. [PMID: 33871826 DOI: 10.1007/s12094-021-02613-w] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022]
Abstract
The year 2019 witnessed the first approval of an immune checkpoint inhibitor (ICI) for the management of triple negative breast cancers (TNBC) that are metastatic and programmed death ligand (PD)-L1 positive. Extensive research has focused on testing ICI-based combinatorial strategies, with the ultimate goal of enhancing the response of breast tumors to immunotherapy to increase the number of breast cancer patients benefiting from this transformative treatment. The promising investigational strategies included immunotherapy combinations with monoclonal antibodies (mAbs) against human epidermal growth factor receptor (HER)-2 for the HER2 + tumors versus cyclin-dependent kinase (CDK)4/6 inhibitors in the estrogen receptor (ER) + disease. Multiple approaches are showing signals of success in advanced TNBC include employing Poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, MEK inhibitors, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) signaling inhibitors or inhibitors of adenosine receptor, in combination with the classical PD-1/PD-L1 immune checkpoint inhibitors. Co-treatment with chemotherapy, high intensity focused ultrasound (HIFU) or interleukin-2-βɣ agonist have also produced promising outcomes. This review highlights the latest combinatorial strategies under development for overcoming cancer immune evasion and enhancing the percentage of immunotherapy responders in the different subsets of advanced breast cancers.
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Affiliation(s)
- M F Tolba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Center of Drug Discovery Research and Development, Ain Shams University, Cairo, 11566, Egypt.
- School of Life and Medical Sciences, University of Hertfordshire-Hosted By Global Academic Foundation, New Capital City, Egypt.
| | - H Elghazaly
- Clinical Oncology Department, and Medical Research Center (MASRI), Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - E Bousoik
- Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Chapman University, Irvine, CA, USA
- School of Pharmacy, Omar-Al-Mukhtar University, Derna, Libya
| | - M M A Elmazar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, The British University in Egypt (BUE), 11837, El Sherouk City, Egypt
| | - S M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
- Harvard Medical School, Boston, MA, USA
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25
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Gasparotto D, Sbaraglia M, Rossi S, Baldazzi D, Brenca M, Mondello A, Nardi F, Racanelli D, Cacciatore M, Paolo Dei Tos A, Maestro R. Tumor genotype, location, and malignant potential shape the immunogenicity of primary untreated gastrointestinal stromal tumors. JCI Insight 2020; 5:142560. [PMID: 33048845 PMCID: PMC7710278 DOI: 10.1172/jci.insight.142560] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 10/07/2020] [Indexed: 12/13/2022] Open
Abstract
Intratumoral immune infiltrate was recently reported in gastrointestinal stromal tumors (GISTs). However, the tumor-intrinsic factors that dictate GIST immunogenicity are still largely undefined. To shed light on this issue, a large cohort (82 samples) of primary untreated GISTs, representative of major clinicopathological variables, was investigated by an integrated immunohistochemical, transcriptomic, and computational approach. Our results indicate that tumor genotype, location, and malignant potential concur to shape the immunogenicity of primary naive GISTs. Immune infiltration was greater in overt GISTs compared with that in lesions with limited malignant potential (miniGISTs), in KIT/PDGFRA-mutated tumors compared with that in KIT/PDGFRA WT tumors, and in PDGFRA-mutated compared with KIT-mutated GISTs. Within the KIT-mutated subset, a higher degree of immune colonization was detected in the intestine. Immune hot tumors showed expression patterns compatible with a potentially proficient but curbed antigen-specific immunity, hinting at sensitivity to immunomodulatory treatments. Poorly infiltrated GISTs, primarily KIT/PDGFRA WT intestinal tumors, showed activation of Hedgehog and WNT/β-catenin immune excluding pathways. This finding discloses a potential therapeutic vulnerability, as the targeting of these pathways might prove effective by both inhibiting pro-oncogenic signals and fostering antitumor immune responses. Finally, an intriguing anticorrelation between immune infiltration and ANO1/DOG1 expression was observed, suggesting an immunomodulatory activity for anoctamin-1.
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Affiliation(s)
- Daniela Gasparotto
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Marta Sbaraglia
- Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padua, Italy
| | - Sabrina Rossi
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Davide Baldazzi
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Monica Brenca
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Alessia Mondello
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Federica Nardi
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Dominga Racanelli
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
| | - Matilde Cacciatore
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Angelo Paolo Dei Tos
- Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padua, Italy
- Department of Medicine, University of Padua School of Medicine, Padua, Italy
| | - Roberta Maestro
- Unit of Oncogenetics and Functional Oncogenomics, Centro di Riferimento Oncologico di Aviano (CRO Aviano) IRCCS, National Cancer Institute, Aviano, Italy
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Baxevanis CN, Fortis SP, Ardavanis A, Perez SA. Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design. Cancers (Basel) 2020; 12:E2908. [PMID: 33050520 PMCID: PMC7600460 DOI: 10.3390/cancers12102908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 12/24/2022] Open
Abstract
Therapeutic cancer vaccines have been at the forefront of cancer immunotherapy for more than 20 years, with promising results in phase I and-in some cases-phase II clinical trials, but with failures in large phase III studies. After dozens of clinical studies, only Dendreon's dendritic cell vaccine Sipuleucel-T has succeeded in receiving US FDA approval for the treatment of metastatic castrate-resistant prostate cancer. Although scientists working on cancer immunotherapy feel that this is an essential breakthrough for the field, they still expect that new vaccine regimens will yield better clinical benefits compared to the four months prolonged median overall survival (OS) Sipuleucel-T demonstrated in the IMPACT phase III clinical trial. Clinical development of cancer vaccines has been unsuccessful due to failures either in randomized phase II or-even worse-phase III trials. Thus, rigorous re-evaluation of these trials is urgently required in order to redefine aspects and optimize the benefits offered by therapeutic cancer vaccines. The scope of this review is to provide to the reader our thoughts on the key challenges in maximizing the therapeutic potentials of cancer vaccines, with a special focus on issues that touch upon clinical trial design.
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Affiliation(s)
- Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
| | - Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
| | - Alexandros Ardavanis
- 1st Medical Oncology Clinic, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece;
| | - Sonia A. Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
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Li HL, Wang LH, Hu YL, Feng Y, Li XH, Liu YF, Li P, Mao QS, Xue WJ. Clinical and prognostic significance of CC chemokine receptor type 8 protein expression in gastrointestinal stromal tumors. World J Gastroenterol 2020; 26:4656-4668. [PMID: 32884223 PMCID: PMC7445867 DOI: 10.3748/wjg.v26.i31.4656] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 06/07/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Surgical resection and tyrosine kinase inhibitors are defined as the main treatments but cannot cure patients with advanced GIST, which eventually develops into recurrence and acquired drug resistance. Therefore, it is necessary to identify prognostic biomarkers and new therapeutic targets for GISTs. CC chemokine receptor type 8 (CCR8) protein participates in regulation of immune responses. Recent studies on CCR8 in non-small cell lung cancer and colorectal cancer showed that it was highly expressed in tumor-infiltrating regulatory T cells and correlated with a poor prognosis.
AIM To detect CCR8 expression in GIST tissues and analyze its relationships with clinicopathological features and prognosis in patients with GISTs.
METHODS Tissue samples were used for the tissue microarrays construction. The microarrays were then subjected to immunohistochemical analyses to detect CCR8 expression. Next, Kaplan–Meier analysis was utilized to calculate the survival rate of patients with complete follow-up data, and the potential prognostic value of CCR8 was evaluated by Cox regression analysis. Finally, a Gene Ontology/Kyoto Encyclopedia of Genes and Genomes single-gene enrichment chart of CCR8 was constructed using the STRING database.
RESULTS CCR8-positive signals were detected as brown or brown-yellow particles by immunohistochemistry located in the cytoplasm. Among 125 tissue samples, 74 had CCR8 high expression and 51 had low or negative expression. Statistical analyses suggested CCR8 was significantly correlated with tumor size, mitotic index, AFIP-Miettinen risk classification and tumor location. Kaplan–Meier and multivariate analyses showed that patients with low or negative CCR8 expression, mitotic index < 5/high-power fields (HPF) and tumor diameter < 5 cm had a better prognosis. Based on the STRING database, CCR8 was significantly enriched in biological processes such as tumor immunity, T lymphocyte chemotaxis, migration and pathways like the nuclear factor-κB and tumor necrosis factor pathways as well as intestinal immune regulation networks.
CONCLUSION CCR8 is a prognostic biomarker for malignant potential of GISTs, with high expression correlated with malignancy and poor prognosis.
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Affiliation(s)
- Huai-Liang Li
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Lin-Hua Wang
- Department of Intensive Care Unit, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Yi-Lin Hu
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Ying Feng
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Xiao-Hong Li
- Department of Surgical Comprehensive Laboratory, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Yi-Fei Liu
- Department of Pathology, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Peng Li
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Qin-Sheng Mao
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
| | - Wan-Jiang Xue
- Department of Gastrointestinal Surgery, Nantong University Affiliated Hospital, Nantong 226001, Jiangsu Province, China
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28
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Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors. Cancer Immunol Immunother 2020; 69:2393-2401. [PMID: 32535637 PMCID: PMC7568699 DOI: 10.1007/s00262-020-02625-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Accepted: 05/28/2020] [Indexed: 02/07/2023]
Abstract
Background The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. Methods The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. Results No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. Conclusion Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registrationwww.clinicaltrials.gov; NCT: 02432846; registration date: February 22, 2016. Electronic supplementary material The online version of this article (10.1007/s00262-020-02625-5) contains supplementary material, which is available to authorized users.
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Rovatti PE, Gambacorta V, Lorentino F, Ciceri F, Vago L. Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation. Front Immunol 2020; 11:147. [PMID: 32158444 PMCID: PMC7052328 DOI: 10.3389/fimmu.2020.00147] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 01/20/2020] [Indexed: 01/05/2023] Open
Abstract
Over the last decade, the development of multiple strategies to allow the safe transfer from the donor to the patient of high numbers of partially HLA-incompatible T cells has dramatically reduced the toxicities of haploidentical hematopoietic cell transplantation (haplo-HCT), but this was not accompanied by a similar positive impact on the incidence of post-transplantation relapse. In the present review, we will elaborate on how the unique interplay between HLA-mismatched immune system and malignancy that characterizes haplo-HCT may impact relapse biology, shaping the selection of disease variants that are resistant to the “graft-vs.-leukemia” effect. In particular, we will present current knowledge on genomic loss of HLA, a relapse modality first described in haplo-HCT and accounting for a significant proportion of relapses in this setting, and discuss other more recently identified mechanisms of post-transplantation immune evasion and relapse, including the transcriptional downregulation of HLA class II molecules and the enforcement of inhibitory checkpoints between T cells and leukemia. Ultimately, we will review the available treatment options for patients who relapse after haplo-HCT and discuss on how a deeper insight into relapse immunobiology might inform the rational and personalized selection of therapies to improve the largely unsatisfactory clinical outcome of relapsing patients.
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Affiliation(s)
- Pier Edoardo Rovatti
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Valentina Gambacorta
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Unit of Senescence in Stem Cell Aging, Differentiation and Cancer, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesca Lorentino
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabio Ciceri
- Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Vita-Salute San Raffaele University, Milan, Italy
| | - Luca Vago
- Unit of Immunogenetics, Leukemia Genomics and Immunobiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Hematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
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30
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Taddei ML, Pietrovito L, Leo A, Chiarugi P. Lactate in Sarcoma Microenvironment: Much More than just a Waste Product. Cells 2020; 9:E510. [PMID: 32102348 PMCID: PMC7072766 DOI: 10.3390/cells9020510] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/20/2020] [Accepted: 02/23/2020] [Indexed: 12/14/2022] Open
Abstract
Sarcomas are rare and heterogeneous malignant tumors relatively resistant to radio- and chemotherapy. Sarcoma progression is deeply dependent on environmental conditions that sustain both cancer growth and invasive abilities. Sarcoma microenvironment is composed of different stromal cell types and extracellular proteins. In this context, cancer cells may cooperate or compete with stromal cells for metabolic nutrients to sustain their survival and to adapt to environmental changes. The strict interplay between stromal and sarcoma cells deeply affects the extracellular metabolic milieu, thus altering the behavior of both cancer cells and other non-tumor cells, including immune cells. Cancer cells are typically dependent on glucose fermentation for growth and lactate is one of the most heavily increased metabolites in the tumor bulk. Currently, lactate is no longer considered a waste product of the Warburg metabolism, but novel signaling molecules able to regulate the behavior of tumor cells, tumor-stroma interactions and the immune response. In this review, we illustrate the role of lactate in the strong acidity microenvironment of sarcoma. Really, in the biological context of sarcoma, where novel targeted therapies are needed to improve patient outcomes in combination with current therapies or as an alternative treatment, lactate targeting could be a promising approach to future clinical trials.
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Affiliation(s)
- Maria Letizia Taddei
- Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Viale Morgagni 50, 50142 Firenze, Italy
| | - Laura Pietrovito
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, Viale Morgagni 50, 50142 Firenze, Italy; (L.P.); (A.L.)
| | - Angela Leo
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, Viale Morgagni 50, 50142 Firenze, Italy; (L.P.); (A.L.)
| | - Paola Chiarugi
- Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Università degli Studi di Firenze, Viale Morgagni 50, 50142 Firenze, Italy; (L.P.); (A.L.)
- Tuscany Tumor Institute and “Center for Research, Transfer and High Education DenoTHE”, 50134 Florence, Italy
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31
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Yoo C, Ryu YM, Kim SY, Kim J, Ock CY, Ryu MH, Kang YK. Association between the exposure to anti-angiogenic agents and tumour immune microenvironment in advanced gastrointestinal stromal tumours. Br J Cancer 2019; 121:819-826. [PMID: 31607749 PMCID: PMC6888806 DOI: 10.1038/s41416-019-0596-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2019] [Accepted: 09/18/2019] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Tumour immune microenvironment (TIME) of gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS A total of 81 surgical specimens from 67 patients with advanced GISTs were categorised into treatment groups: tyrosine kinase inhibitor (TKI)-naive, n = 20; imatinib-progressed and no exposure to sunitinib or regorafenib (IM-PD), n = 30; and imatinib-progressed and sunitinib and/or regorafenib-treated (IM-PD/SU-treated), n = 31. Multiplexed immunofluorescence staining and RNA sequencing were performed to define TIME. RESULTS PD-L1 expression rate (>1%) of DOG-1+ tumour cells was 5.0, 6.7, and 29.0% in TKI-naive, IM-PD, and IM-PD/SU-treated group, respectively (p = 0.02). FoxP3 expression of CD3+ T cells and CD204+ CD68+ monocytes per DOG-1+ cells was significantly higher in IM-PD/SU-treated group compared to TKI-naive and IM-PD groups (p < 0.05). IM-PD/SU-treated group showed increased expression of PD-1 on CD3+ T cells (p = 0.03 vs TKI-naive; p = 0.003 vs IM-PD) and DOG-1+ tumour cells (p = 0.02 vs TKI-naive; p = 0.006 vs IM-PD), TIM-3 expression on CD3+ T cells (p = 0.01 vs TKI-naive; p = 0.002 vs IM-PD), and LAG3 expression on CD3+ T cells (p = 0.001 vs TKI-naive; p = 0.004 vs IM-PD). In the RNAseq analysis, TIGIT expression was significantly increased in IM-PD/SU-treated GISTs compared to IM-PD (p = 0.01). CONCLUSION Immunosuppressive phenotype was predominant in tumours treated with anti-angiogenic agents compared to TKI-naive and IM-treated tumours.
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Affiliation(s)
- Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yeon-Mi Ryu
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang-Yeob Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jihun Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | | | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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32
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Pantaleo MA, Tarantino G, Agostinelli C, Urbini M, Nannini M, Saponara M, Castelli C, Stacchiotti S, Fumagalli E, Gatto L, Santini D, De Leo A, Marafioti T, Akarca A, Sabattini E, Pession A, Ardizzoni A, Indio V, Astolfi A. Immune microenvironment profiling of gastrointestinal stromal tumors (GIST) shows gene expression patterns associated to immune checkpoint inhibitors response. Oncoimmunology 2019; 8:e1617588. [PMID: 31428517 PMCID: PMC6685519 DOI: 10.1080/2162402x.2019.1617588] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/30/2019] [Accepted: 05/01/2019] [Indexed: 01/05/2023] Open
Abstract
Few studies were conducted investigating the immunological profiles in gastrointestinal stromal tumors (GIST). Adaptive and innate immune cells are present in the tumor microenvironment, indicating GIST as inflamed tumors. In addition, murine models suggested a potential interaction between immune components and imatinib. In this retrospective study, the GIST immunological profile was investigated through in silico analysis and immunohistochemistry (IHC), exploring the basis for immunotherapy approaches. Gene expression profiles (GEP) from 31 KIT/PDGFRA-mutant GIST were analyzed to evaluate the tumor microenvironment and immunotherapy predictive signatures such as the expanded IFN-γ-induced immune signature (EIIS) and the T-cell-inflamed signature (TIS). GEP and IHC supported the presence of immune infiltrate in GIST, with dominance of CD4+ and CD8+ T cells and M2 macrophages showing a remarkable similarity with melanoma microenvironment. The EIIS genes were expressed in most of GIST samples and positively correlated with PD-L1 abundance (p < .0001). Co-expression was also found between PD-L1 and CD8A (p < .0001) or CD8B (p = .0003). Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1. Analysis of the Gene Expression Omnibus database GIST samples pre- and post-treatment confirmed that imatinib downregulates PD-L1 and IRF1 expression through the inhibition of KIT and PDGFRA, thus contributing to counteract the suppressed adaptive immune response against GIST. The presence of a rich immune infiltrate in GIST along with the presence of TIS and EIIS suggests that GIST may benefit from immunotherapy along with tyrosine kinase inhibitors.
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Affiliation(s)
- Maria A. Pantaleo
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Giuseppe Tarantino
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
| | - Claudio Agostinelli
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Milena Urbini
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
| | - Margherita Nannini
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Maristella Saponara
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Chiara Castelli
- Unit of Immunotherapy of Human Tumours, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Silvia Stacchiotti
- Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Elena Fumagalli
- Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Lidia Gatto
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Donatella Santini
- Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Antonio De Leo
- Pathology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Teresa Marafioti
- Department of Histopathology, University College London, University College Hospital
| | - Ayse Akarca
- Department of Histopathology, University College London, University College Hospital
| | - Elena Sabattini
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Andrea Pession
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna Italy
| | - Andrea Ardizzoni
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy
| | - Valentina Indio
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- “Giorgio Prodi” Cancer Research Center (CIRC), University of Bologna, Bologna, Italy
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Longo V, Brunetti O, Azzariti A, Galetta D, Nardulli P, Leonetti F, Silvestris N. Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review. Cancers (Basel) 2019; 11:cancers11040539. [PMID: 30991686 PMCID: PMC6521062 DOI: 10.3390/cancers11040539] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/11/2019] [Accepted: 04/12/2019] [Indexed: 12/27/2022] Open
Abstract
Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.
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Affiliation(s)
- Vito Longo
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Oronzo Brunetti
- Medical Oncology Unit, Hospital of Barletta, Viale Ippocrate, 15, 70051 Barletta, Italy.
| | - Amalia Azzariti
- Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Domenico Galetta
- Medical Thoracic Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Patrizia Nardulli
- Pharmacy Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
| | - Francesco Leonetti
- Dipartimento di Farmacia-Scienze del Farmaco, University of Bari, Piazza Umberto I, 1, 70121 Bari, Italy.
| | - Nicola Silvestris
- Scientific Guidance, IRCCS Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 Bari, Italy.
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Rakaee M, Busund LTR, Jamaly S, Paulsen EE, Richardsen E, Andersen S, Al-Saad S, Bremnes RM, Donnem T, Kilvaer TK. Prognostic Value of Macrophage Phenotypes in Resectable Non-Small Cell Lung Cancer Assessed by Multiplex Immunohistochemistry. Neoplasia 2019; 21:282-293. [PMID: 30743162 PMCID: PMC6369140 DOI: 10.1016/j.neo.2019.01.005] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/14/2019] [Accepted: 01/17/2019] [Indexed: 12/14/2022] Open
Abstract
Macrophages are important inflammatory cells that regulate innate and adaptive immunity in cancer. Tumor-associated macrophages (TAMs) are thought to differentiate into two main phenotypes: proinflammatory M1 and protumorigenic M2. Currently, the prognostic impact of TAMs and their M1 and M2 phenotypes is unclear in non–small cell cancer (NSCLC). The present study was set up to evaluate an approach for identifying common M1 and M2 macrophage markers and explore their clinical significance in NSCLC. Using multiplex chromogenic immunohistochemistry, tissue microarrays of 553 primary tumors and 143 paired metastatic lymph nodes of NSCLC specimens were stained to detect various putative macrophage phenotypes: M1 (HLA-DR/CD68), M2 (CD163/CD68), M2 (CD204/CD68), and pan-macrophage (CD68/CK). Correlation analyses were performed to examine the relationship between TAMs and adaptive/innate immune infiltrates. HLA-DR+/CD68+M1 TAM level significantly decreased from pathological stage I to III. In a compartment-specific correlation analysis, moderate to strong correlations were observed between both TAM subsets (M1 and M2) with CD3-, CD8-, CD4-, and CD45RO-positive immune cells. Survival analyses, in both stromal and intratumoral compartments, revealed that high levels of HLA-DR+/CD68+M1 (stroma, hazard ratio [HR] = 0.73, P = .03; intratumor, HR = 0.7, P = .04), CD204+M2 (stroma, HR = 0.7, P = .02; intratumor, HR = 0.6, P = .004), and CD68 (stroma, HR = 0.69, P = .02; intratumor, HR = 0.73, P = .04) infiltration were independently associated with improved NSCLC-specific survival. In lymph nodes, the intratumoral level of HLA-DR+/CD68+M1 was an independent positive prognostic indicator (Cox model, HR = 0.38, P = .001). In conclusion, high levels of M1, CD204+M2, and CD68 macrophages are independent prognosticators of prolonged survival in NSCLC.
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Affiliation(s)
- Mehrdad Rakaee
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019.
| | - Lill-Tove Rasmussen Busund
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Simin Jamaly
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019.
| | - Erna-Elise Paulsen
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Elin Richardsen
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Sigve Andersen
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Samer Al-Saad
- Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Roy M Bremnes
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Tom Donnem
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
| | - Thomas K Kilvaer
- Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway, 9019; Department of Oncology, University Hospital of North Norway, Tromsø, Norway, 9019.
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Addressing the Adult Soft Tissue Sarcoma Microenvironment with Intratumoral Immunotherapy. Sarcoma 2018; 2018:9305294. [PMID: 30158830 PMCID: PMC6109466 DOI: 10.1155/2018/9305294] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023] Open
Abstract
Sarcoma is comprised of a heterogeneous group of tumors originating from the mesenchyme. Sarcoma is also the first tumor that responded to immunotherapeutic agents often termed as “Coley's toxins.” However, immunotherapy is yet to establish its presence in sarcomas. Complex interactions between tumor and immune cells in the tumor microenvironment play a crucial role in response to immunotherapy. There is a dynamic equilibrium created by the immune cells infiltrating the tumor, and this forms the basis of tumor evasion. Manipulating the intratumoral microenvironment will help overcome tumor evasion.
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Zhu C, Kros JM, Cheng C, Mustafa D. The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies. Neuro Oncol 2018; 19:1435-1446. [PMID: 28575312 DOI: 10.1093/neuonc/nox081] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
"Tumor-associated macrophages" (TAMs) form a significant cell population in malignant tumors and contribute to tumor growth, metastasis, and neovascularization. Gliomas are characterized by extensive neo-angiogenesis, and knowledge of the role of TAMs in neovascularization is important for future anti-angiogenic therapies. The phenotypes and functions of TAMs are heterogeneous and more complex than a classification into M1 and M2 inflammation response types would suggest. In this review, we provide an update on the current knowledge of the ontogeny of TAMs, focusing on diffuse gliomas. The role of TAMs in the regulation of the different processes in tumor angiogenesis is highlighted and the most recently discovered mechanisms by which TAMs mediate resistance against current antivascular therapies are mentioned. Novel compounds tested in clinical trials are discussed and brought in relation to different TAM-related angiogenesis pathways. In addition, potential therapeutic targets used to intervene in TAM-regulated tumor angiogenesis are summarized.
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Affiliation(s)
- Changbin Zhu
- Department of Pathology, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, Netherlands; Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht, Utrecht, Netherlands
| | - Johan M Kros
- Department of Pathology, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, Netherlands; Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht, Utrecht, Netherlands
| | - Caroline Cheng
- Department of Pathology, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, Netherlands; Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht, Utrecht, Netherlands
| | - Dana Mustafa
- Department of Pathology, Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, Netherlands; Department of Nephrology and Hypertension, DIGD, University Medical Center Utrecht, Utrecht, Netherlands
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Li H, Meng QH, Noh H, Somaiah N, Torres KE, Xia X, Batth IS, Joseph CP, Liu M, Wang R, Li S. Cell-surface vimentin-positive macrophage-like circulating tumor cells as a novel biomarker of metastatic gastrointestinal stromal tumors. Oncoimmunology 2018; 7:e1420450. [PMID: 29721368 PMCID: PMC5927484 DOI: 10.1080/2162402x.2017.1420450] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 12/12/2017] [Accepted: 12/17/2017] [Indexed: 01/28/2023] Open
Abstract
The clinical utility of circulating tumor cells (CTCs) has been investigated in numerous publications, but CTCs that express very typical immune cell markers have not been reported. Here we report a novel class of CTCs-CSV-positive macrophage-like CTCs (ML-CTCs). This nomenclature was based on the fact that this class of CTCs can be captured from blood samples of gastrointestinal stromal tumors (GISTs) patients using either the macrophage marker CD68 or our proprietary tumor-specific cell-surface vimentin (CSV) antibody 84-1; likewise, the captured ML-CTCs can be co-stained with both typical macrophage markers (CD14, CD68) and tumor cell markers (DOG-1, C-kit) but not CD45. Patients with metastatic GIST had significantly greater numbers of ML-CTCs than patients with localized GIST or cancer-free blood donors (P<0.0001). Unexpectedly, the classic CSV positive CTCs was abundant in metastatic disease but failed to predict GIST metastasis. Only CSV-positive ML-CTCs was able to serve as a solid and novel biomarker for prediction of metastatic risk in GIST patients.
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Affiliation(s)
- Heming Li
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian, Liaoning Province, China
| | - Qing H Meng
- Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Hyangsoon Noh
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Keila E Torres
- Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Xueqing Xia
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Izhar S Batth
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Cissimol P Joseph
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX USA
| | - Mengyuan Liu
- Department of Gastroenterology and Endoscopy, First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Ruoyu Wang
- Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning Province, China.,The Key Laboratory of Biomarker High Throughput Screening and Target Translation of Breast and Gastrointestinal Tumor, Dalian, Liaoning Province, China
| | - Shulin Li
- Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX USA
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A BRCA1 deficient, NFκB driven immune signal predicts good outcome in triple negative breast cancer. Oncotarget 2017; 7:19884-96. [PMID: 26943587 PMCID: PMC4991425 DOI: 10.18632/oncotarget.7865] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 02/18/2016] [Indexed: 12/31/2022] Open
Abstract
Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or ‘BRCAness’, is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success. This reflects the significant problem of accurately detecting those patients with BRCA1 dysfunction. Moreover, not all BRCA1 mutations/loss of function result in the same histology/pathology or indeed have similar effects in modulating therapeutic responses. Given the poor clinical outcomes and lack of targeted therapy for these subtypes, a better understanding of the biology underlying these diseases is required in order to develop novel therapeutic strategies. We have discovered a consistent NFκB hyperactivity associated with BRCA1 dysfunction as a consequence of increased Reactive Oxygen Species (ROS). This biology is found in a subset of BRCA1-mutant and triple negative breast cancer cases and confers good outcome. The increased NFκB signalling results in an anti-tumour microenvironment which may allow CD8+ cytotoxic T cells to suppress tumour progression. However, tumours lacking this NFκB-driven biology have a more tumour-promoting environment and so are associated with poorer prognosis. Tumour-derived gene expression data and cell line models imply that these tumours may benefit from alternative treatment strategies such as reprogramming the microenvironment and targeting the IGF and AR signalling pathways.
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Handl M, Hermanova M, Hotarkova S, Jarkovsky J, Mudry P, Shatokhina T, Vesela M, Sterba J, Zambo I. Clinicopathological correlation of tumor-associated macrophages in Ewing sarcoma. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2017; 162:54-60. [PMID: 29170560 DOI: 10.5507/bp.2017.049] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/26/2017] [Indexed: 02/07/2023] Open
Abstract
AIMS Tumor-associated macrophages (TAMs) are known markers playing complex roles in tumorigenesis. However, the function of TAMs in a variety of malignancies is not yet fully understood. The aim of this pilot study was to quantify the density of TAMs in Ewing sarcoma and to determine the correlation between TAMs and clinicopathological parameters. METHODS Using immunohistochemistry, the expressions of CD68 and CD163 were examined in 24 tissue samples of Ewing sarcoma of bone. The density of CD68 and CD163-positive TAMs was analyzed quantitatively and semi-quantitatively and statistically correlated with clinical parameters. RESULTS CD163-positive TAMs outnumbered CD68-positive cells (median of 130 vs 96, respectively). No statistically significant relatio nship was found between density of CD68-positive cells, clinical parameters or prognosis. However, high levels of CD163-positive TAMs were associated with localized disease (P=0.008). In cases with a higher density of CD163-positive cells, a trend toward longer survival was revealed (P=0.063). CONCLUSION This is the first study that has quantified CD163 expression in TAMs in Ewing sarcoma and showed its possible prognostic value. CD163 was confirmed to be a more specific marker of macrophages than CD68. CD163 is not an exclusive hallmark of M2 macrophages.
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Affiliation(s)
- Marek Handl
- Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Marketa Hermanova
- 1st Department of Pathological Anatomy, Faculty of Medicine, Masaryk University, Brno and St. Anne's University Hospital, Brno, Czech Republic
| | - Sylva Hotarkova
- 1st Department of Pathological Anatomy, Faculty of Medicine, Masaryk University, Brno and St. Anne's University Hospital, Brno, Czech Republic
| | - Jiri Jarkovsky
- Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic
| | - Peter Mudry
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Tetiana Shatokhina
- 1st Department of Pathological Anatomy, Faculty of Medicine, Masaryk University, Brno and St. Anne's University Hospital, Brno, Czech Republic
| | - Marcela Vesela
- 1st Department of Pathological Anatomy, Faculty of Medicine, Masaryk University, Brno and St. Anne's University Hospital, Brno, Czech Republic
| | - Jaroslav Sterba
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Iva Zambo
- 1st Department of Pathological Anatomy, Faculty of Medicine, Masaryk University, Brno and St. Anne's University Hospital, Brno, Czech Republic
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Kostine M, Briaire-de Bruijn IH, Cleven AHG, Vervat C, Corver WE, Schilham MW, Van Beelen E, van Boven H, Haas RL, Italiano A, Cleton-Jansen AM, Bovée JVMG. Increased infiltration of M2-macrophages, T-cells and PD-L1 expression in high grade leiomyosarcomas supports immunotherapeutic strategies. Oncoimmunology 2017; 7:e1386828. [PMID: 29308311 PMCID: PMC5749622 DOI: 10.1080/2162402x.2017.1386828] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 09/25/2017] [Accepted: 09/26/2017] [Indexed: 10/25/2022] Open
Abstract
Background: Immunotherapy may be a rational strategy in leiomyosarcoma (LMS), a tumor known for its genomic complexity. As a prerequisite for therapeutic applications, we characterized the immune microenvironment in LMS, as well as its prognostic value. Methods: CD163+ macrophages, CD3+ T-cells, PD-L1/PD-L2 and HLA class I expression (HCA2, HC10 and β2m) were evaluated using immunohistochemistry in primary tumors (n = 75), local relapses (n = 6) and metastases (n = 19) of 87 LMS patients, as well as in benign leiomyomas (n = 7). Correlation with clinicopathological parameters and survival analyses were assessed. Effect of LMS cells on macrophage differentiation was investigated using coculture of CD14+ monocytes with LMS cell lines or their conditioned media (CM). Results: 58% and 52% of the tumors were highly infiltrated with CD163+ macrophages and T-cells, respectively, with HLA class I expression observed in almost all tumors and PD-L1 expression in 30%. PD-L2 expression was also detected in some PD-L1+ tumors. All these immune markers correlated with high tumor grade but only CD163 associated with overall survival (p = 0.003) and disease-specific survival (p = 0.041). In vitro, CD163 was upregulated in the presence of LMS cells producing M-CSF, suggesting that this tumor drives macrophages towards the M2 phenotype. Conclusion: The clinical significance of M2 macrophages, possibly induced by LMS cell-secreted factors, suggests that 2/3 of high-grade LMS patients might benefit from macrophage-targeting agents. Furthermore, PD-L1 expression together with high T-cell infiltrate and HLA class I expression in around 30% of high grade LMS reflects an active immune microenvironment potentially responsive to immune checkpoint inhibitors.
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Affiliation(s)
- Marie Kostine
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.,Department of Rheumatology, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France
| | | | - Arjen H G Cleven
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Carly Vervat
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Willem E Corver
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marco W Schilham
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
| | - Els Van Beelen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, ZA Leiden, The Netherlands
| | - Hester van Boven
- Department of Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | - Rick L Haas
- Department of Radiotherapy, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, The Netherlands.,Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands
| | - Antoine Italiano
- Department of Medical Oncology, Institut Bergonié, Bordeaux, France
| | | | - Judith V M G Bovée
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
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Rusakiewicz S, Perier A, Semeraro M, Pitt JM, Pogge von Strandmann E, Reiners KS, Aspeslagh S, Pipéroglou C, Vély F, Ivagnes A, Jegou S, Halama N, Chaigneau L, Validire P, Christidis C, Perniceni T, Landi B, Berger A, Isambert N, Domont J, Bonvalot S, Terrier P, Adam J, Coindre JM, Emile JF, Poirier-Colame V, Chaba K, Rocha B, Caignard A, Toubert A, Enot D, Koch J, Marabelle A, Lambert M, Caillat-Zucman S, Leyvraz S, Auclair C, Vivier E, Eggermont A, Borg C, Blay JY, Le Cesne A, Mir O, Zitvogel L. NKp30 isoforms and NKp30 ligands are predictive biomarkers of response to imatinib mesylate in metastatic GIST patients. Oncoimmunology 2016; 6:e1137418. [PMID: 28197361 DOI: 10.1080/2162402x.2015.1137418] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 12/21/2015] [Accepted: 12/28/2015] [Indexed: 12/31/2022] Open
Abstract
Despite effective targeted therapy acting on KIT and PDGFRA tyrosine kinases, gastrointestinal stromal tumors (GIST) escape treatment by acquiring mutations conveying resistance to imatinib mesylate (IM). Following the identification of NKp30-based immunosurveillance of GIST and the off-target effects of IM on NK cell functions, we investigated the predictive value of NKp30 isoforms and NKp30 soluble ligands in blood for the clinical response to IM. The relative expression and the proportions of NKp30 isoforms markedly impacted both event-free and overall survival, in two independent cohorts of metastatic GIST. Phenotypes based on disbalanced NKp30B/NKp30C ratio (ΔBClow) and low expression levels of NKp30A were identified in one third of patients with dismal prognosis across molecular subtypes. This ΔBClow blood phenotype was associated with a pro-inflammatory and immunosuppressive tumor microenvironment. In addition, detectable levels of the NKp30 ligand sB7-H6 predicted a worse prognosis in metastatic GIST. Soluble BAG6, an alternate ligand for NKp30 was associated with low NKp30 transcription and had additional predictive value in GIST patients with high NKp30 expression. Such GIST microenvironments could be rescued by therapy based on rIFN-α and anti-TRAIL mAb which reinstated innate immunity.
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Affiliation(s)
- Sylvie Rusakiewicz
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France
| | - Aurélie Perier
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France
| | - Michaela Semeraro
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Department of Pediatric Oncology, GRCC, Villejuif, France
| | - Jonathan M Pitt
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France
| | | | - Katrin S Reiners
- Department of Internal Medicine I, University Hospital of Cologne , Cologne, Germany
| | - Sandrine Aspeslagh
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France
| | - Christelle Pipéroglou
- Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille , Marseille, France
| | - Frédéric Vély
- Hôpital de la Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France; INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France
| | - Alexandre Ivagnes
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France
| | - Sarah Jegou
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France
| | - Niels Halama
- Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, Heidelberg, Germany; National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - Loic Chaigneau
- Department of Medical Oncology, Centre Hospitalier Universitaire Jean Minjoz , Besançon, France
| | - Pierre Validire
- Department of Pathology, Institut Mutualiste Montsouris, Paris, France; Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France
| | - Christos Christidis
- Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris, Paris, France; Department of Surgery, Institut Mutualiste Montsouris, University of Paris Descartes 5, Paris, France
| | - Thierry Perniceni
- Department of Medical Oncology, Sarcoma, Institut Mutualiste Montsouris , Paris, France
| | - Bruno Landi
- Department of Gastroenterology and Digestive Oncology, Georges Pompidou European Hospital, University of Paris Descartes 5 , Paris, France
| | - Anne Berger
- Department of Surgery, Georges Pompidou European Hospital, University of Paris Descartes , Paris, France
| | - Nicolas Isambert
- Department of Medical Oncology, Centre Georges-François Leclerc , Dijon, France
| | - Julien Domont
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France
| | - Sylvie Bonvalot
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France; Department of Surgery, GRCC, Villejuif, France
| | - Philippe Terrier
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France; Department of Pathology, GRCC, Villejuif, France; Center of Biological Resources, GRCC, Villejuif, France
| | - Julien Adam
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Pathology, GRCC, Villejuif, France; Center of Biological Resources, GRCC, Villejuif, France
| | | | | | - Vichnou Poirier-Colame
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France
| | - Kariman Chaba
- Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
| | - Benedita Rocha
- INSERM, U1020, Paris, France; Faculté de Médecine René Descartes, Paris, France
| | - Anne Caignard
- INSERM, U1160, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France
| | - Antoine Toubert
- INSERM, U1160, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France
| | - David Enot
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; INSERM, U1138, Paris, France; Metabolomics and Cell Biology platforms, GRCC, Villejuif, France
| | - Joachim Koch
- Institute of Medical Microbiology and Hygiene, University of Mainz Medical Centre , Mainz, Germany
| | - Aurélien Marabelle
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Drug Development Department (DITEP), GRCC, Villejuif, France
| | - Marion Lambert
- INSERM, U1149, Equipe "Immunité innée chez l'enfant", Hôpital Robert Debré , Paris, France
| | - Sophie Caillat-Zucman
- INSERM, U1149, Equipe "Immunité innée chez l'enfant", Hôpital Robert Debré , Paris, France
| | - Serge Leyvraz
- Department of Oncology, University Hospital , Lausanne, Switzerland
| | - Christian Auclair
- Applied Biology and Pharmacology Laboratory, Ecole Normale Supèrieur of Cachan , Cachan, France
| | - Eric Vivier
- INSERM, U1104, Centre d'Immunologie de Marseille-Luminy, Marseille, France; CNRS, UMR7280, Marseille, France; Aix Marseille Université, UM2, Marseille, France
| | | | | | - Jean-Yves Blay
- Department of Medicine, Centre Léon Bérard & Université Claude Bernard Lyon I, DGOS-INCA SIRIC , Lyon, France
| | - Axel Le Cesne
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France
| | - Olivier Mir
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; Department of Medicine, Sarcoma committee, GRCC, Villejuif, France
| | - Laurence Zitvogel
- Gustave Roussy Cancer Campus (GRCC), Villejuif, France; INSERM, U1015, IGR, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT), Villejuif, France; University of Paris Sud XI, Villejuif, France
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42
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Ang C, Maki RG. Contemporary Management of Metastatic Gastrointestinal Stromal Tumors: Systemic and Locoregional Approaches. Oncol Ther 2016; 4:1-16. [PMID: 28261637 PMCID: PMC5315077 DOI: 10.1007/s40487-015-0014-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Indexed: 12/25/2022] Open
Abstract
The treatment of metastatic gastrointestinal stromal tumors (GISTs) changed dramatically with the introduction of imatinib into the therapeutic lexicon in 2001. Over the past 15 years, tyrosine kinase inhibitors in the adjuvant and metastatic settings have remained the standard of care for this disease, though alternate classes of agents and new therapeutic targets are being actively explored in clinical trials. Although data are limited, the use of surgical and non-surgical locoregional techniques for the treatment of GIST metastases has increased and given reports of promising and durable responses. Herein we provide an overview of the contemporary therapeutic landscape of metastatic GIST.
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Affiliation(s)
- Celina Ang
- Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
| | - Robert G Maki
- Division of Hematology/Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA
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Mori K, Haraguchi S, Hiori M, Shimada J, Ohmori Y. Tumor-associated macrophages in oral premalignant lesions coexpress CD163 and STAT1 in a Th1-dominated microenvironment. BMC Cancer 2015; 15:573. [PMID: 26242181 PMCID: PMC4525742 DOI: 10.1186/s12885-015-1587-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 07/27/2015] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Tumor-associated macrophages (TAMs) are implicated in the growth, invasion and metastasis of various solid tumors. However, the phenotype of TAMs in premalignant lesions of solid tumors has not been clarified. In the present study, we identify the phenotype of TAMs in leukoplakia, an oral premalignant lesion, by immunohistochemical analysis and investigate the involvement of infiltrated T cells that participate in the polarization of TAMs. METHODS The subjects included 30 patients with oral leukoplakia and 10 individuals with normal mucosa. Hematoxylin and eosin slides were examined for the histological grades, and immunohistochemical analysis was carried out using antibodies against CD68 (pan-MΦ), CD80 (M1 MΦ), CD163 (M2 MΦ), CD4 (helper T cells: Th), CD8 (cytotoxic T cells), CXCR3, CCR5 (Th1), CCR4 (Th2), signal transducer and activator of transcription (STAT1), phosphorylated STAT1 (pSTAT1) and chemokine CXCL9. The differences in the numbers of positively stained cells among the different histological grades were tested for statistical significance using the Kruskal-Wallis test. Correlations between different types of immune cells were determined using Spearman's rank analysis. RESULTS An increase in the rate of CD163(+) TAM infiltration was observed in mild and moderate epithelial dysplasia, which positively correlated with the rate of intraepithelial CD4(+) Th cell infiltration. Although CCR4(+) cells rarely infiltrated, CXCR3(+) and CCR5(+) cells were observed in these lesions. Cells positive for STAT1 and chemokine CXCL9, interferon- (IFN)-induced gene products, and pSTAT1 were also observed in the same lesions. Double immunofluorescence staining demonstrated that the cells that were positive for CD163 were also positive for STAT1. CONCLUSIONS CD163(+) TAMs in oral premalignant lesions coexpress CD163 and STAT1, suggesting that the TAMs in oral premalignant lesions possess an M1 phenotype in a Th1-dominated micromilieu.
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Affiliation(s)
- Kazumasa Mori
- Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics Sciences, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama, 350-0283, Japan.
| | - Shigeki Haraguchi
- Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics Sciences, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama, 350-0283, Japan.
| | - Miki Hiori
- Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama, 350-0283, Japan.
| | - Jun Shimada
- Division of Oral and Maxillofacial Surgery, Department of Diagnosis and Therapeutics Sciences, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama, 350-0283, Japan.
| | - Yoshihiro Ohmori
- Division of Microbiology and Immunology, Department of Oral Biology and Tissue Engineering, Meikai University of School of Dentistry, 1-1 Keyakidai, Sakado, Saitama, 350-0283, Japan.
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Abstract
Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted.
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Affiliation(s)
- Xiaofei Yu
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Chunqing Guo
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - John R Subjeck
- Department of Cellular Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
| | - Xiang-Yang Wang
- Department of Human and Molecular Genetics, Richmond, Virginia, USA; VCU Institute of Molecular Medicine, Richmond, Virginia, USA; VCU Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
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Abstract
OPINION STATEMENT The management of advanced gastrointestinal stromal tumor (GIST) has been dramatically altered by the development of tyrosine kinase inhibitors. The disease, which had a median overall survival of 12 months for patients with unresectable disease, now has a median survival approaching 5 or more years. The challenge faced clinically is how to care for patients when they have progressed on all approved therapies. Clinical trials evaluating the role of novel combination therapies with investigational agents that target AKT/PI3K pathways are of interest especially given the preclinical rationale available. The addition of an mTOR inhibitor can be tried as these are available, but requires care and monitoring for additional toxicities. With improved understanding of this disease, which we thought of as one biology, personalized therapies are being studied and tested and is particularly relevant for GIST that are less responsive to the standard kinase inhibitors, such as platelet-derived growth factor alpha (PDGFRA) D842V and wild-type/succinate dehydrogenase (SDH)-deficient GIST. IGF1R inhibitors as a class are not being developed because of the lack of significant efficacy in many clinical trials and the efficacy in WT GIST has been limited; to date drugs targeting VEGFR, such as sunitinib and regorafenib, appear to be the best agents available for this group of patients. The exciting findings seen with CTLA4 and PD-1/PD-L1 antibodies in melanoma and other solid tumors is exciting, especially because there is a growing body of evidence that such approaches have biologic rationale; clinical trials evaluating these agents are awaited with interest. Last, recent work has shed light on older agents that may have a role in GIST. Moving forward to test these agents alone or in combination with TKIs offers potentially new strategies for treating advanced disease.
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Affiliation(s)
- Natthapol Songdej
- Department of Medical Oncology and Hematology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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46
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Bertucci F, Finetti P, Mamessier E, Pantaleo MA, Astolfi A, Ostrowski J, Birnbaum D. PDL1 expression is an independent prognostic factor in localized GIST. Oncoimmunology 2015; 4:e1002729. [PMID: 26155391 DOI: 10.1080/2162402x.2014.1002729] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 12/22/2014] [Accepted: 12/23/2014] [Indexed: 01/18/2023] Open
Abstract
Gastrointestinal stromal tumors (GIST) are the most frequently occurring digestive sarcomas. The prognosis of localized GIST is heterogeneous, notably for patients with an Armed Forces Institute of Pathology (AFIP) intermediate or high risk of relapse. Despite imatinib effectiveness, it is crucial to develop therapies able to overcome the resistance mechanisms. The immune system represents an attractive prognostic and therapeutic target. The Programmed cell Death 1 (PD1)/programmed cell death ligand 1 (PDL1) pathway is a key inhibitor of the immune response; recently, anti-PD1 and anti-PDL1 drugs showed very promising results in patients with solid tumors. However, PDL1 expression has never been studied in GIST. Our objective was to analyze PDL1 expression in a large series of clinical samples. We analyzed mRNA expression data of 139 operated imatinib-untreated localized GIST profiled using DNA microarrays and searched for correlations with histoclinical features including postoperative metastatic relapse. PDL1 expression was heterogeneous across tumors and was higher in AFIP low-risk than in high-risk samples, and in samples without than with metastatic relapse. PDL1 expression was associated with immunity-related parameters such as T-cell-specific and CD8+ T-cell-specific gene expression signatures and probabilities of activation of interferon α (IFNα), IFNγ, and tumor necrosis factor α (TNFα) pathways, suggesting positive correlation with a cytotoxic T-cell response. In multivariate analysis, the PDL1-low group was associated with a higher metastatic risk independently of the AFIP classification and the KIT mutational status. In conclusion, PDL1 expression refines the prediction of metastatic relapse in localized GIST and might improve our ability to better tailor adjuvant imatinib. In the metastatic setting, PDL1 expression might guide the use of PDL1 inhibitors, alone or associated with tyrosine kinase inhibitors.
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Key Words
- AFIP, Armed Forces Institute of Pathology
- DNA microarray
- FDR, false discovery rate
- GEO, gene expression omnibus
- GES, gene expression signatures
- GIST
- GIST, gastrointestinal stromal tumors
- GO, gene ontology
- IHC, immunohistochemistry
- ISH, in situ hybridization
- MFS, metastasis-free survival
- MHC, major histocompatibility complex
- NCBI, National Center for Biotechnology Information
- NK cells, natural killer cells
- PCA, principal component analysis
- PD1, programmed cell death 1
- PDGFRA, platelet-derived growth factor receptor α
- PDL1
- PDL1, programmed cell death ligand 1
- REMARK, REcommendations for tumor MARKer
- RMA, robust multichip average
- ROC, receiver operating characteristic
- TILs, tumor-infiltrating lymphocytes
- Treg, regulatory T cells
- WT, wild type
- gene expression
- immune response
- prognosis
- qRT-PCR, quantitative reverse transcription-polymerase chain reaction
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Affiliation(s)
- François Bertucci
- Department of Molecular Oncology; Institut Paoli-Calmettes; Centre de Recherche en Cancérologie de Marseille ; UMR1068 Inserm; Marseille, France ; Aix-Marseille University ; Marseille, France ; French Sarcoma Group ; Lyon, France
| | - Pascal Finetti
- Department of Molecular Oncology; Institut Paoli-Calmettes; Centre de Recherche en Cancérologie de Marseille ; UMR1068 Inserm; Marseille, France
| | - Emilie Mamessier
- Department of Molecular Oncology; Institut Paoli-Calmettes; Centre de Recherche en Cancérologie de Marseille ; UMR1068 Inserm; Marseille, France
| | - Maria Abbondanza Pantaleo
- Department of Specialized, Experimental and Diagnostic Medicine; Sant'Orsola-Malpighi Hospital ; Bologna, Italy
| | - Annalisa Astolfi
- Giorgio Prodi Cancer Research Center; University of Bologna ; Bologna, Italy
| | - Jerzy Ostrowski
- Department of Gastroenterology and Hepatology; Cancer Center-Institute and Medical Center of Postgraduate Education ; Warsaw, Poland
| | - Daniel Birnbaum
- Department of Molecular Oncology; Institut Paoli-Calmettes; Centre de Recherche en Cancérologie de Marseille ; UMR1068 Inserm; Marseille, France
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Espagnolle N, Barron P, Mandron M, Blanc I, Bonnin J, Agnel M, Kerbelec E, Herault JP, Savi P, Bono F, Alam A. Specific Inhibition of the VEGFR-3 Tyrosine Kinase by SAR131675 Reduces Peripheral and Tumor Associated Immunosuppressive Myeloid Cells. Cancers (Basel) 2014; 6:472-90. [PMID: 24589997 PMCID: PMC3980599 DOI: 10.3390/cancers6010472] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 02/06/2014] [Accepted: 02/17/2014] [Indexed: 12/16/2022] Open
Abstract
Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) represent prominent components in cancer progression. We previously showed that inhibition of the VEGFR-3 pathway by SAR131675 leads to reduction of TAM infiltration and tumor growth. Here, we found that treatment with SAR131675 prevents the accumulation of immunosuppressive blood and splenic MDSCs which express VEGFR-3, in 4T1 tumor bearing mice. Moreover we showed that soluble factors secreted by tumor cells promote MDSCs proliferation and differentiation into M2 polarized F4/80+ macrophages. In addition, cell sorting and transcriptomic analysis of tumor infiltrating myeloid cells revealed the presence of a heterogeneous population that could be divided into 3 subpopulations: (i) immature cells with a MDSC phenotype (GR1+/CD11b+/F4/80−); (ii) “immuno-incompetent” macrophages (F4/80high/CD86neg/MHCIILow) strongly expressing M2 markers such as Legumain, CD206 and Mgl1/2 and (iii) “immuno-competent”-M1 like macrophages (F4/80Low/CD86+/MHCIIHigh). SAR131675 treatment reduced MDSCs in lymphoid organs as well as F4/80High populations in tumors. Interestingly, in the tumor SAR131675 was able to increase the immunocompetent M1 like population (F4/80low). Altogether these results demonstrate that the specific VEGFR-3 inhibitor SAR131675 exerts its anti tumoral activity by acting on different players that orchestrate immunosuppression and cancer progression in a tumoral context: MDSCs in peripheral lymphoid organs and TAMs infiltrating the tumor.
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Affiliation(s)
| | - Pauline Barron
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Marie Mandron
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Isabelle Blanc
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Jacques Bonnin
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Magali Agnel
- Molecular Biology Unit, Biologics Department, Sanofi, Vitry-sur-Seine 94400, France.
| | - Erwan Kerbelec
- Molecular Biology Unit, Biologics Department, Sanofi, Vitry-sur-Seine 94400, France.
| | - Jean Pascal Herault
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Pierre Savi
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Françoise Bono
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
| | - Antoine Alam
- Sanofi Recherche et Développement, Early to Candidate DPU, Toulouse 31036, France.
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Kim TS, Cavnar MJ, Cohen NA, Sorenson EC, Greer JB, Seifert AM, Crawley MH, Green BL, Popow R, Pillarsetty N, Veach DR, Ku AT, Rossi F, Besmer P, Antonescu CR, Zeng S, Dematteo RP. Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res 2014; 20:2350-62. [PMID: 24583793 DOI: 10.1158/1078-0432.ccr-13-3033] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. EXPERIMENTAL DESIGN We treated Kit(V558del/+) mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. RESULTS PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit(V558del)(/+) murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. CONCLUSIONS PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.
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Affiliation(s)
- Teresa S Kim
- Authors' Affiliations: Departments of Surgery, Radiology, Developmental Biology, and Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
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Galmarini CM, D'Incalci M, Allavena P. Trabectedin and plitidepsin: drugs from the sea that strike the tumor microenvironment. Mar Drugs 2014; 12:719-33. [PMID: 24473171 PMCID: PMC3944511 DOI: 10.3390/md12020719] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 01/13/2014] [Accepted: 01/14/2014] [Indexed: 12/25/2022] Open
Abstract
The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up-regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment.
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Affiliation(s)
- Carlos M Galmarini
- Cell Biology and Pharmacogenomics Department, PharmaMar, Madrid 28770, Spain.
| | - Maurizio D'Incalci
- Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan 20156, Italy.
| | - Paola Allavena
- Department Immunology and Inflammation, IRCCS Clinical and Research Institute Humanitas, Rozzano, Milan 20089, Italy.
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50
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Cavnar MJ, Zeng S, Kim TS, Sorenson EC, Ocuin LM, Balachandran VP, Seifert AM, Greer JB, Popow R, Crawley MH, Cohen NA, Green BL, Rossi F, Besmer P, Antonescu CR, DeMatteo RP. KIT oncogene inhibition drives intratumoral macrophage M2 polarization. ACTA ACUST UNITED AC 2013; 210:2873-86. [PMID: 24323358 PMCID: PMC3865475 DOI: 10.1084/jem.20130875] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
Imatinib reduces tumor cell KIT signaling and causes tumor cell apoptosis, which drives TAMs to shift from M1- to M2-like in mouse and human GIST. Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.
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Affiliation(s)
- Michael J Cavnar
- Department of Surgery, 2 Department of Developmental Biology, and 3 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
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