Journal Article

Lack of interleukin‐6 in the tumor microenvironment augments type‐1 immunity and increases the efficacy of cancer immunotherapy

Ohno, Yosuke, Toyoshima, Yujiro, Kaneumi, Shun, Kitamura, Hidemitsu, Sumida, Kentaro, Terada, Satoshi, Hashimoto, Shinichi, Yurino, Hideaki, Taketomi, Akinobu, Homma, Shigenori, Ikeo, Kazuho, Takahashi, Norihiko, Kawamura, Hideki, Monma, Norikazu, Xiang, Huihui

2017

Overview

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies. IL‐6 produced in the tumor hosts suppresses antitumor immunity involving the activation of effector T cells and dendritic cells. Lack of IL‐6 facilitates cancer immunotherapies using immune checkpoint inhibitors and immunological adjuvants.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Antibodies, Monoclonal - administration & dosage / Antibodies, Monoclonal - pharmacology / Antibodies, Monoclonal, Humanized / Antigens / Antitumor activity / Apoptosis / Cancer immunotherapy / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Cloning / Colon cancer / Colonic Neoplasms - genetics / Colonic Neoplasms - immunology / Colonic Neoplasms - therapy / Colorectal cancer / Cytokines / Cytotoxic T cells / Cytotoxicity / Dendritic cells / Dendritic Cells - immunology / Drug Synergism / Effector cells / Fibroblasts / Flow cytometry / Gene expression / Gene Expression Regulation, Neoplastic / Immune status / Immunoglobulins / Immunology / Immunosuppression / Immunotherapy / Immunotherapy - methods / Interferon / Interferon-gamma - metabolism / interferon‐γ / Interleukin-6 - deficiency / Interleukin-6 - genetics / interleukin‐6 / Kinases / Laboratory animals / Ligands / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Mice / Microenvironments / Original / PD-L1 protein / programmed death‐ligand 1 / Studies / T-Lymphocytes, Cytotoxic - immunology / T-Lymphocytes, Helper-Inducer - immunology / Toll-like receptors / Tumor Microenvironment - drug effects / Tumorigenesis / Xenograft Model Antitumor Assays