Nishiwaki et al. focused on mechanisms underlying the immunosuppressive effects of cancer-associated fibroblasts (CAFs) in the TME. In patient samples of esophageal cancer, high IL-6 levels correlated with significantly shorter OS, tumor immunosuppression, and increased numbers of αSMA+CAFs and immunosuppressive TAMs. In syngeneic tumor models, MR16-1 (anti-IL-6R Ab) suppressed tumor growth, increased CD8+ T cells, and decreased HIF-1α+ expression and activation. Mechanistically, CAF-produced IL-6 increased HIF1α expression, creating competition for glucose in the TME via activation of GLUT-1 and upregulation of VEGF.
Contributed by Katherine Turner
ABSTRACT: Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with _-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1_ (HIF1_) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1_ activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1_ activation.
Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558
Author Info: (1) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (2) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. knoma@md.okayama-u.ac.jp. (3) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. Department of Pathology & Experimental Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan. (4) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (5) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (6) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (7) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (8) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (9) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (10) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (11) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (12) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (13) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (14) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (15) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. (16) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan. (17) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan. Department of Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan. (18) Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-ku, Okayama, 700-8558, Japan.
