Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-05, Vol.77 (9), p.2279-2291
• Main Authors: Tsukamoto, Hirotake, Fujieda, Koji, Hirayama, Masatoshi, Ikeda, Tokunori, Yuno, Akira, Matsumura, Keiko, Fukuma, Daiki, Araki, Kimi, Mizuta, Hiroshi, Nakayama, Hideki, Senju, Satoru, Nishimura, Yasuharu
• Format: Article
• Language: English
• Subjects: Animals; Antitumor activity; Auditory defects; Blood circulation; c-Maf protein; Cancer; Cancer immunotherapy; Carcinogenesis - genetics; CD11b antigen; CD4 antigen; CD4-Positive T-Lymphocytes - pathology; CD8 antigen; Clonal deletion; Gene Expression Regulation, Neoplastic; Humans; Immunosuppression; Immunotherapy; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - genetics; Lymphocytes; Lymphocytes T; Medical prognosis; Mice; Molecular Targeted Therapy; Myeloid cells; Myeloid Cells - metabolism; Myeloid Cells - pathology; Neoplasms - genetics; Neoplasms - pathology; Proto-Oncogene Proteins c-maf - genetics; Receptors, Interleukin-6 - genetics; Th1 Cells; Tumor cells
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-2446

IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4 T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8 T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4 T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy. .