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

Abstract

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.

Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity

“…Direct action of IL‐6 has been evidenced by STAT3 activation in CD4 + T cells and myeloid cells, and their activation was diminished by IL‐6 blockade, implying that these cells are attractive targets for IL‐6‐mediated immune regulation in tumor‐bearing mice and cancer patients . Our group and others demonstrated using different models that IL‐6 blockade significantly improved the differentiation of CD4 + T cells into IFN‐γ‐producing effector Th1 cells in tumor‐bearing mice in response to immunotherapies such as DC vaccination or immune‐checkpoint blockade . Targeted deletion or specific inhibition of sIL‐6R also rescued the attenuation of Th1 differentiation .…”

“…[17][18][19][20] Our group and others demonstrated using different models that IL-6 blockade significantly improved the differentiation of CD4 + T cells into IFN-cproducing effector Th1 cells in tumor-bearing mice in response to immunotherapies such as DC vaccination or immune-checkpoint blockade. 17,22,23,30 Targeted deletion or specific inhibition of sIL-6R also rescued the attenuation of Th1 differentiation. 17 Thus, systemically increased IL-6/sIL-6R in tumor-bearing hosts is responsible for the impaired Th1 responses which are often observed in cancer patients.…”

“…IL‐6 conversely inhibits the expression of MHC‐II, CD80/86, and IL‐12 in DC or re‐programs the differentiation into IL‐10‐producing regulatory DC . These immune‐suppressive effects on myeloid cells consequently compromised their ability to trigger the activation of Th1 cells and CTL . Furthermore, IL‐6 promotes differentiation into M2 macrophages, which also amplify the immune‐suppressive effects, and limit the anti‐tumor T‐cell responses (Figure ).…”

“…21 These immune-suppressive effects on myeloid cells consequently compromised their ability to trigger the activation of Th1 cells and CTL. 30,40 Furthermore, IL-6 promotes differentiation into M2 macrophages, 39 which also amplify the immune-suppressive effects, and limit the anti-tumor T-cell responses (Figure 1). From a different perspective, it is very likely that Th2-biased differentiation of IL-6-sensitized CD4 + T cells contributes to the skewing toward the pro-tumorigenic M2 macrophages through IL-4 production.…”

“…However, the inhibition of IL-6/ sIL-6R-mediated signaling combined with other therapeutic approaches has been the next promising subject of intense investigation, as already shown in preclinical mouse models. 23,30 Encouraging this aim, recent clinical studies demonstrated that the higher level of IL-6 was significantly associated with a lower overall survival rate of cancer patients vaccinated with TAA, 58 although IL-6 is a prognostic factor irrespective of treatment, 14,18 and thus may not necessarily be predictive and unique to immunotherapy. Nevertheless, by virtue of mechanisms in which disruption of the IL-6/ STAT3/c-Maf axis confers a "resetting" of the Th1/Th2 imbalance in tumor-specific CD4 + T cells, simultaneously combined use of IL-6-targeting reagents that improves the quality of tumor-specific T cells can be a promising strategy for further enhancement of efficacy in current T-cell-based immunotherapies beyond their simply compensating for the quantitative decrease in T cells (Figure 4).…”