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Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy
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 underlyin...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507498/ https://www.ncbi.nlm.nih.gov/pubmed/32994996 http://dx.doi.org/10.1002/cti2.1168 |
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author | Kim, Ji‐Hae Kim, Young‐Min Choi, Donghoon Jo, Saet‐byeol Park, Han Wook Hong, Sung‐Wook Park, Sujeong Kim, Sora Moon, Sookjin You, Gihoon Kang, Yeon‐Woo Park, Yunji Lee, Byung Ha Lee, Seung‐Woo |
author_facet | Kim, Ji‐Hae Kim, Young‐Min Choi, Donghoon Jo, Saet‐byeol Park, Han Wook Hong, Sung‐Wook Park, Sujeong Kim, Sora Moon, Sookjin You, Gihoon Kang, Yeon‐Woo Park, Yunji Lee, Byung Ha Lee, Seung‐Woo |
author_sort | Kim, Ji‐Hae |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7507498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-75074982020-09-28 Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy Kim, Ji‐Hae Kim, Young‐Min Choi, Donghoon Jo, Saet‐byeol Park, Han Wook Hong, Sung‐Wook Park, Sujeong Kim, Sora Moon, Sookjin You, Gihoon Kang, Yeon‐Woo Park, Yunji Lee, Byung Ha Lee, Seung‐Woo Clin Transl Immunology Original Article 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. John Wiley and Sons Inc. 2020-09-04 /pmc/articles/PMC7507498/ /pubmed/32994996 http://dx.doi.org/10.1002/cti2.1168 Text en © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Article Kim, Ji‐Hae Kim, Young‐Min Choi, Donghoon Jo, Saet‐byeol Park, Han Wook Hong, Sung‐Wook Park, Sujeong Kim, Sora Moon, Sookjin You, Gihoon Kang, Yeon‐Woo Park, Yunji Lee, Byung Ha Lee, Seung‐Woo Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title | Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title_full | Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title_fullStr | Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title_full_unstemmed | Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title_short | Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
title_sort | hybrid fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507498/ https://www.ncbi.nlm.nih.gov/pubmed/32994996 http://dx.doi.org/10.1002/cti2.1168 |
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