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.

• Authors: 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
• Journal: Clinical & translational immunology (Clin Transl Immunology) Vol. 9 Issue 9 Pg. e1168 ( 2020) ISSN: 2050-0068 [Print] Australia
• PMID: 32994996 (Publication Type: Journal Article)
• 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.