Sjögren's syndrome (SS) is a chronic inflammatory autoimmune disorder that affects mainly salivary and lacrimal glands, but its cause remains largely unknown. Clinical data indicating that SS occurs in a substantial proportion of patients with lupus points to common pathogenic mechanisms underlying the two diseases. To address this idea, we asked whether SS develops in the lupus-prone mouse strain sanroque (SAN). Owing to hyper-activation of follicular helper T (Tfh) cells, female SAN mice developed lupus-like symptoms at approximately 20 wk of age but there were no signs of SS at that time. However, symptoms typical of SS were evident at approximately 40 wk of age, as judged by reduced saliva flow rate, sialadenitis, and IgG deposits in the salivary glands. Increases in serum titers of SS-related autoantibodies and numbers of autoantibody-secreting cells in cervical lymph nodes (LNs) preceded the pathologic manifestations of SS and were accompanied by expansion of Tfh cells and their downstream effector cells. Thus, our results suggest that chronic dysregulation of Tfh cells in salivary gland-draining LNs is sufficient to drive the development of SS in lupus-prone mice.
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.
A remarkable progress of cancer immunotherapy in a recent decade, including immune checkpoint blockades (ICB), has shed a new light on the medical treatment of cancer patients. These successes of immunotherapies affirm the notion that modulation of immune-related environment, although not directly targeting a tumor cell, might lead to a better efficacy for cancer treatment. Interleukine-7 (IL-7), a member of the common γ chain family cytokine, plays important roles in the development and homeostasis of lymphocytes in both mouse and human, in particular T lymphocytes. Positive effects of recombinant IL-7 on anti-tumor activity in preclinical models have placed IL-7 as a strong candidate for a novel immunotherapeutic agent in clinics; however, a short half-life of recombinant protein has remained a challenge. Here, we investigated anti-tumor effects in mice of the long-acting form of recombinant human IL-7 fused with hybrid Fc (IL-7-hyFc) in syngeneic tumor models. A dramatic inhibition of tumor growth was achieved when IL-7-hyFc is given in a single subcutaneous injection with palpable tumor burdens. IL-7-hyFc administration significantly enhanced the expression level of CXCR3 on T cells and the frequency of CD8+ tumor-infiltrating lymphocytes (TILs). Of interest, the fraction of PD-1+CD8+ TILs was decreased by IL-7-hyFc, with the cell surface level of PD-1 being diminished. Therefore, IL-7-hyFc is able to expand tumor antigen specific CD8+ effector T cells, resulting in the enhanced infiltration and functional recuperation of TILs. Nonetheless, the tumor growth inhibition by IL-7-hyFc was not observed in mice with large tumor burdens. To increase the therapeutic efficacy of IL-7-hyFc in this model, we combined single injection of the conventional chemotherapeutics cyclophosphamide (CTX) with a moderate dose in which CTX confers immunogenic tumor cell death without severely depleting immune compartment. The combinatorial treatment with IL-7-hyFc and CTX augmented the infiltration of CD8+ TILs, leading to an increased survival in a large established tumor model. In sum, IL-7-hyFc confers the effective anti-tumor responses through reconstructing CD8+ T lymphocytes; this activity was limited when the tumor burden was high but restored along with combination with the chemotherapeutics. Thus, these results imply that IL-7-hyFc can be applied to various cancer immunotherapy regimens as monotherapy or a combination partner with conventional and other immunotherapy, like ICB. Citation Format: Ji-Hae Kim, Donghoon Choi, Man Kyu Ji, Seat-byeul Jo, Han Wook Park, Yeon Kyung Oh, Youngmin Kim, Hyekang Kim, Byung Ha Lee, Se Hwan Yang, Young Chul Sung, Seung-Woo Lee. Preclinical evaluation of the anti-tumor activity of Fc-fused interleukin-7 in both monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1731.
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