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

Clin Transl Immunology. 2020 Sep 4;9(9):e1168. doi: 10.1002/cti2.1168. eCollection 2020.

Authors

Ji-Hae Kim¹, Young-Min Kim¹, Donghoon Choi², Saet-Byeol Jo³, Han Wook Park³, Sung-Wook Hong^{4

5}, Sujeong Park³, Sora Kim³, Sookjin Moon³, Gihoon You³, Yeon-Woo Kang³, Yunji Park³, Byung Ha Lee², Seung-Woo Lee^{1

3}

Affiliations

¹ Laboratory of Cellular Immunology Department of Life Sciences Pohang University of Science and Technology Pohang Korea.
² Research Institute of NeoImmuneTech, Inc. Rockville MD USA.
³ Laboratory of Cellular Immunology Division of Integrative Biosciences and Biotechnology Pohang University of Science and Technology Pohang Korea.
⁴ Laboratory of T Cell Biology Division of Integrative Biosciences and Biotechnology Pohang University of Science and Technology Pohang Korea.
⁵ Department of Microbiology and Immunology Center for Immunology University of Minnesota Medical School Minneapolis MN USA.

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.

Keywords: cytokine; immunotherapy; interleukin‐7; lymphopenia; rhIL‐7‐hyFc; tumor microenvironment.