Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX 77054.
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054.
J Immunol. 2021 Apr 15;206(8):1966-1975. doi: 10.4049/jimmunol.2000523. Epub 2021 Mar 15.
Inflammation has long been associated with cancer initiation and progression; however, how inflammation causes immune suppression in the tumor microenvironment and resistance to immunotherapy is not well understood. In this study, we show that both innate proinflammatory cytokine IL-1α and immunotherapy-induced IL-1α make melanoma resistant to immunotherapy. In a mouse melanoma model, we found that tumor size was inversely correlated with response to immunotherapy. Large tumors had higher levels of IL-1α, Th2 cytokines, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and regulatory T cells but lower levels of IL-12, Th1 cytokines, and activated T cells. We found that therapy with adenovirus-encoded CD40L (rAd.CD40L) increased tumor levels of IL-1α and PMN-MDSCs. Blocking the IL-1 signaling pathway significantly decreased rAd.CD40L-induced PMN-MDSCs and their associated PD-L1 expression in the tumor microenvironment and enhanced tumor-specific immunity. Similarly, blocking the IL-1 signaling pathway improved the antimelanoma activity of anti-PD-L1 Ab therapy. Our study suggests that blocking the IL-1α signaling pathway may increase the efficacy of immunotherapies against melanoma.
炎症长期以来一直与癌症的发生和发展有关；然而，炎症如何导致肿瘤微环境中的免疫抑制以及对免疫疗法的耐药性尚不清楚。在这项研究中，我们表明先天促炎细胞因子 IL-1α 和免疫治疗诱导的 IL-1α 使黑色素瘤对免疫疗法产生耐药性。在小鼠黑色素瘤模型中，我们发现肿瘤大小与对免疫疗法的反应呈反比。大肿瘤具有更高水平的 IL-1α、Th2 细胞因子、多形核髓系来源的抑制性细胞（PMN-MDSCs）和调节性 T 细胞，但 IL-12、Th1 细胞因子和活化 T 细胞水平较低。我们发现，用编码 CD40L 的腺病毒（rAd.CD40L）治疗可增加肿瘤中 IL-1α 和 PMN-MDSCs 的水平。阻断 IL-1 信号通路可显著减少 rAd.CD40L 诱导的肿瘤微环境中的 PMN-MDSCs 及其相关的 PD-L1 表达，并增强肿瘤特异性免疫。同样，阻断 IL-1 信号通路可提高抗 PD-L1 Ab 治疗对黑色素瘤的疗效。我们的研究表明，阻断 IL-1α 信号通路可能会提高针对黑色素瘤的免疫疗法的疗效。
