Abstract 3213: Combination of anti-IL-6 and anti-PD-L1 antibodies synergistically reinvigorates cancer immunity by activating both CTL and Th1 cells in mice
Authors: Nishimura Yasuharu , Fujieda Koji , Miyashita Azusa , Fukushima Satoshi , Ikeda Tokunori , Kubo Yosuke , Senju Satoru , Ihn Hironobu , Oshiumi Hiroyuki , Tsukamoto Hirotake 
Published: August 2019

Abstract
We previously demonstrated that Th1 differentiation of tumor-specific CD4+ T cells was attenuated in tumor-bearing or aged mice in an IL-6-dependent manner (Nat. Comm. 6: e6702, 2015, Cancer Immunol. Res. 1: 64, 2013). Furthermore we found that accompanied by the systemic increase of soluble IL-6 receptor (sIL-6R) in cancer patients, inhibition of IL-6 trans-signaling mediated through the sIL-6R restored the Th1 responses, their helper activity toward CD8+ T cells, and anti-tumor activity in tumor-bearing mice (Cancer Res. 77: 2279, 2017). The systemically increased sIL-6Rs were mainly produced by myeloid cells. Moreover, cMaf-deficient CD4+ T cells were resistant to Th1 suppression and impairment of T cell-mediated anti-tumor immunity induced by IL-6/sIL-6R indicating that c-Maf activity was responsible for Th1 suppression. Myeloid cell-derived sIL-6R was also possibly associated with Th1 suppression and c-Maf expression in head and neck cancer patients. These results suggest that targeting a pro-inflammatory cytokine, IL-6 enhanced the tumor-specific Th1 responses and subsequent anti-tumor effects. However, IL-6 blockade in turn up-regulated the expression of immune-checkpoint molecule, PD-L1 on melanoma cells. This PD-L1 induction was canceled in IFN-γ-deficient mice or mice depleted of CD4+ T cells, suggesting an important role of CD4+ T cell-derived IFN-γ in the PD-L1 induction in tumor-bearing hosts. On the other hand, in some patients with melanoma, anti-PD-1 antibody, Nivolumab treatment increased the systemic level of IL-6, which were associated with their poor clinical responses. This PD-L1 blockade-evoked IL-6 induction was also observed in melanoma-bearing mice (Cancer Res. 78: 5011, 2018). Considering the mechanistic linkage between IL-6 and PD-1/PD-L1 signals, we found that PD-1/PD-L1 blockade prompted PD-1+macrophages to produce IL-6 in tumor microenvironment. Depletion of macrophages in melanoma-bearing mice revealed that macrophages functioned as a source of IL-6 during PD-L1 blockade, which was responsible for the defective Th1 response. Furthermore, combined blockade of the mutually regulated-immunosuppressive activities mediated by IL-6 and PD-1/PD-L1 signals enhanced the infiltration of IFN-γ-producing CD4+ T cells in tumor tissues, and exerted a synergistic anti-tumor effect, whereas PD-L1 blockade alone did not promote Th1 response. Collectively, these findings suggest that IL-6 is considered to be a rational immunosuppressive target to overcome a narrow therapeutic window of anti-PD-1/PD-L1 therapy. [ This research was financially supported by the JSPS KAKENHI grant nos. 26430165 and 18K07325 to HT, nos. 15H04311 and 16H06498 to YN, and the P-CREATE from the AMED, Japan to YN and HT. ]
Citation Format: Yasuharu Nishimura, Koji Fujieda, Azusa Miyashita, Satoshi Fukushima, Tokunori Ikeda, Yosuke Kubo, Satoru Senju, Hironobu Ihn, Hiroyuki Oshiumi, Hirotake Tsukamoto. Combination of anti-IL-6 and anti-PD-L1 antibodies synergistically reinvigorates cancer immunity by activating both CTL and Th1 cells in mice [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 3213.