Interleukine-7 (IL-7), a strong candidate for a novel immunotherapeutic agent, plays important roles in the development and homeostasis of T lymphocytes. Recombinant IL-7 has shown positive effects in various models by increasing T cells in both mice and humans; however, the short half-life and stability of recombinant IL-7 has remained a challenge for its clinical application to cancer immunotherapy. Here, we investigated anti-tumor effects of a long-acting form of recombinant human IL-7 fused with hybrid Fc (rhIL-7-hyFc; Hyleukin-7) in mice. rhIL-7-hyFc administration in tumor-free mice generated the cytokine-induced CD8+ T cell proliferation, which altering CD8+ T cell homeostasis by expanding largely the TCM-phenotype CD8+ T cells displaying activation-induced attributes, such as Eomes, Granzyme B, CXCR3, and IFN-γ. When injected into mice with syngeneic tumor graft, rhIL-7-hyFc induced anti-tumor activity in a dose-dependent manner. rhIL-7-hyFc dramatically expands CD8+ T cells in the periphery and recruits effector CD8+ T cells in the tumor, yielding a high CD8+ T/Treg cell ratio in the tumor microenvironment (TME). rhIL-7-hyFc increases Ki-67 and granzyme-B expression but decreases expression levels of immune checkpoint molecules on CD8+ tumor-infiltrating lymphocytes (TILs). Surprisingly, rhIL-7-hyFc reduced myeloid-derived suppressor cells (MDSCs) in the TME, yielding the high CD8+ T/MDSC ratio. Collectively, rhIL-7-hyFc treatment confers anti-cancer activity by inducing a “CD8+ T cell infiltrated-inflamed-immune favorable” TME. The combination treatment of rhIL-7-hyFc with cyclophosphamide and immune checkpoint blockades showed enhanced anti-tumor efficacy in an advanced tumor model. Furthermore, we found that the anti-tumor activity of rhIL-7-hyFc was achieved under lymphopenic conditions by normalizing CD8+ T cell homeostasis. In sum, rhIL-7-hyFc generates an effective anti-tumor response through reconstructing CD8+ T lymphocytes; this activity was highly enhanced by combination therapies with the chemotherapeutics and immune checkpoint blockades. Our data suggests that rhIL-7-hyFc can be applied to various cancer immunotherapy regimens as a monotherapy or in combination partner with conventional and other immunotherapies.

Citation Format: Ji-Hae Kim, Sung-Wook Hong, Young-Min Kim, Saet-byeul Jo, Man Kyu Ji, Yeon Kyung Oh, Han Wook Park, Sora Kim, Donghoon Choi, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Seung-Woo Lee. Hyleukin-7, the Fc-fused interleukin-7, generates anti-tumor activity by modulating both adaptive and innate immune cells in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4991.