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

Ji Hae Kim; Young Min Kim; Donghoon Choi; Saet byeol Jo; Han Wook Park; Sung Wook Hong; Sujeong Park; Sora Kim; Sookjin Moon; Gihoon You; Yeon Woo Kang; Yunji Park; Byung Ha Lee; Seung Woo Lee

doi:10.1002/cti2.1168

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

Ji Hae Kim, Young Min Kim, Donghoon Choi, Saet byeol Jo, Han Wook Park, Sung Wook Hong, Sujeong Park, Sora Kim, Sookjin Moon, Gihoon You, Yeon Woo Kang, Yunji Park, Byung Ha Lee, Seung Woo Lee

Division of Life Sciences

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e1168
Journal	Clinical and Translational Immunology
Volume	9
Issue number	9
DOIs	https://doi.org/10.1002/cti2.1168
Publication status	Published - 2020

Bibliographical note

Funding Information:
We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL-7-hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL-7-hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc.

Funding Information:
We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL‐7‐hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL‐7‐hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc.

Publisher Copyright:
© 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

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Immunology and Allergy
Immunology

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10.1002/cti2.1168

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Kim, J. H., Kim, Y. M., Choi, D., Jo, S. B., Park, H. W., Hong, S. W., Park, S., Kim, S., Moon, S., You, G., Kang, Y. W., Park, Y., Lee, B. H., & Lee, S. W. (2020). Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy. Clinical and Translational Immunology, 9(9), [e1168]. https://doi.org/10.1002/cti2.1168

@article{33b44cb46eaa4651bed4ea869f617de4,

title = "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.",

author = "Kim, {Ji Hae} and Kim, {Young Min} and Donghoon Choi and Jo, {Saet byeol} and Park, {Han Wook} and Hong, {Sung Wook} and Sujeong Park and Sora Kim and Sookjin Moon and Gihoon You and Kang, {Yeon Woo} and Yunji Park and Lee, {Byung Ha} and Lee, {Seung Woo}",

note = "Funding Information: We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL-7-hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL-7-hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc. Funding Information: We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL‐7‐hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL‐7‐hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc. Publisher Copyright: {\textcopyright} 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.",

year = "2020",

doi = "10.1002/cti2.1168",

language = "English",

volume = "9",

journal = "Clinical and Translational Immunology",

issn = "2050-0068",

publisher = "Nature Publishing Group",

number = "9",

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TY - JOUR

T1 - Hybrid Fc-fused interleukin-7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

AU - Kim, Ji Hae

AU - Kim, Young Min

AU - Choi, Donghoon

AU - Jo, Saet byeol

AU - Park, Han Wook

AU - Hong, Sung Wook

AU - Park, Sujeong

AU - Kim, Sora

AU - Moon, Sookjin

AU - You, Gihoon

AU - Kang, Yeon Woo

AU - Park, Yunji

AU - Lee, Byung Ha

AU - Lee, Seung Woo

N1 - Funding Information: We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL-7-hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL-7-hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc. Funding Information: We thank Man Kyu Ji and Yeon Kyung Oh (Genexine, Inc.) for supporting experiments. We thank Young Chul Sung (Genexine, Inc.) for helpful advice and providing cancer cell lines. We thank Jaehan Park and Se Hwan Yang (NeoImmuneTech, Inc.) for helpful advice and support, specifically the supply of rhIL‐7‐hyFc and its formulation buffer reagents. We thank Songa Lim and Haejin Jung for their technical assistance. We thank all members of the rhIL‐7‐hyFc science meeting from Genexine for helpful advice. This work was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (2017M3A9C8033570), by BK21 Plus funded by the Ministry of Education, Korea (10Z20130012243), and by Research Institute of NeoImmuneTech, Inc. Publisher Copyright: © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

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UN SDGs

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