Ohno et al. showed that tumor growth in IL-6-deficient mice was suppressed compared to wild-type mice due to augmented infiltration of cytotoxic T cells and mature dendritic cells into the tumor microenvironment. Lack of IL-6 further enhanced the antitumor effect of anti-PD-L1 therapy, suggesting that blocking IL-6 signaling may be a promising approach in cancer immunotherapy.
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 this 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)-gamma-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-gamma 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. This article is protected by copyright. All rights reserved.
Author Info: (1) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. Department of
Author Info: (1) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (2) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (3) Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641. (4) DNA Data Analysis Laboratory, National Institute of Genetics, 1111 Yata, Mishima, 411-8540. (5) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. (6) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. (7) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. (8) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815. (9) Department of Integrative Medicine for Longevity, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641. (10) DNA Data Analysis Laboratory, National Institute of Genetics, 1111 Yata, Mishima, 411-8540. (11) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (12) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (13) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (14) Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-8638. (15) Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo, 060-0815.
