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Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy.

ABSTRACT: Objectives:Emerging oncotherapeutic strategies require the induction of an immunostimulatory tumor microenvironment (TME) containing numerous tumor-reactive CD8+ T cells. Interleukin-7 (IL-7), a T-cell homeostatic cytokine, induces an antitumor response; however, the detailed mechanisms underlying the contributions of the IL-7 to TME remain unclear. Here, we aimed to investigate the mechanism underlying the induction of antitumor response by hybrid Fc-fused long-acting recombinant human IL-7 (rhIL-7-hyFc) through regulation of both adaptive and innate immune cells in the TME. Methods:We evaluated rhIL-7-hyFc-mediated antitumor responses in murine syngeneic tumor models. We analysed the cellular and molecular features of tumor-infiltrating lymphocytes (TILs) and changes in the TME after rhIL-7-hyFc treatment. Furthermore, we evaluated the antitumor efficacy of rhIL-7-hyFc combined with chemotherapy and checkpoint inhibitors (CPIs). Results:Systemic delivery of rhIL-7-hyFc induced significant therapeutic benefits by expanding CD8+ T cells with enhanced tumor tropism. In tumors, rhIL-7-hyFc increased both tumor-reactive and bystander CD8+ TILs, all of which displayed enhanced effector functions but less exhausted phenotypes. Moreover, rhIL-7-hyFc suppressed the generation of immunosuppressive myeloid cells in the bone marrow of tumor-bearing mice, resulting in the immunostimulatory TME. Combination therapy with chemotherapy and CPIs, rhIL-7-hyFc elicited a strong antitumor response and even under a T lymphopenic condition by restoring CD8+ T cells. When combined with chemotherapy and CPIs, rhIL-7-hyFc administration enhanced antitumor response under intact andlymphopenic conditions by restoring CD8+ T cells. Conclusion:Taken together, these data demonstrate that rhIL-7-hyFc induces antitumor responses by generating T-cell-inflamed TME and provide a preclinical proof of concept of immunotherapy with rhIL-7-hyFc to enhance therapeutic responses in the clinic.

SUBMITTER: Kim JH

PROVIDER: S-EPMC7507498 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy.

Kim Ji-Hae JH Kim Young-Min YM Choi Donghoon D Jo Saet-Byeol SB Park Han Wook HW Hong Sung-Wook SW Park Sujeong S Kim Sora S Moon Sookjin S You Gihoon G Kang Yeon-Woo YW Park Yunji Y Lee Byung Ha BH Lee Seung-Woo SW

Clinical & translational immunology 20200904 9

<h4>Objectives</h4>Emerging oncotherapeutic strategies require the induction of an immunostimulatory tumor microenvironment (TME) containing numerous tumor-reactive CD8<sup>+</sup> T cells. Interleukin-7 (IL-7), a T-cell homeostatic cytokine, induces an antitumor response; however, the detailed mechanisms underlying the contributions of the IL-7 to TME remain unclear. Here, we aimed to investigate the mechanism underlying the induction of antitumor response by hybrid Fc-fused long-acting recombi ...[more]

PMID: 32994996

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Project description:BackgroundPatients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.MethodsWe established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort.ResultsTwo patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance.ConclusionsThe TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.

Project description:BackgroundImmunotherapy has shown great potential for the treatment of multiple cancer and has been proven to be closely related to the tumor microenvironment. This article reveals collaborations and interactions among authors, nations, organizations, and periodicals assesses the knowledge base, and discovers hot tendencies and new topics associated with immunotherapy-tumor microenvironment (TME) research.MethodsThis article utilized bibliometrics and visual methods to provide a comprehensive overview of immunotherapy-TME research. Our team retrieved the WoSCC for research and reviews associated with immunotherapy and the tumor microenvironment. VOSviewer and Citespace were primarily used for literature measurement and knowledge graph analysis.ResultAll English articles and reviews on cancer immunotherapy effectiveness were collected, and 1,419 academic journals with 53,773 authors from 7,008 institutions in 92 countries/regions were found. Publications associated with immunotherapy-TME research were stably increasing. Frontiers of Immunology (n = 722) published the most papers on immunotherapy-TME, and Cancer Research (n = 6761) was the top co-cited journal. The published journals and co-cited journals focused on cancer and immunology fields. The League of European Research Universities (n = 978), Harvard University (n = 528), and the University of Texas system (n = 520) were the most productive institutions. Yang Liu (n = 34) and Topalian (n = 1978) ranked first among the top 10 scholars and co-cited scholars. Simultaneously, immunotherapy-TME researchers were involved in active collaborations. Elements of TME, the foundation of immunotherapy, and the application of immunotherapy in cancers represented the three principal aspects of immunotherapy-TME research. The latest hot spots are drug resistance, prognosis prediction, efficacy prediction, and m6A. Nanomedicine and m6A may be future hot topics. Future research in immunotherapy-TME may be directed at discovering how m6A modification affects tumor development by altering the tumor microenvironment and exploring how to enhance response or reduce drug resistance to immunotherapy by reversing or mediating the physicochemical properties of the TME.ConclusionsM6A and nanomedicine are also emerging hotspots in time zone diagrams with high centrality, and prognosis prediction using bioinformatics based on the development of prediction technology may be another future research hotspot.

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Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy.

Publications

Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy.

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