Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
复制标题
DOI：
10.1158/2159-8290.cd-19-0672
复制
发表时间：
2020-02-01
期刊：
影响因子：
28.2
通讯作者：
Aplin, Andrew E.
中科院分区：
文献类型：
--
作者：
Erkes, Dan A.;Cai, Weijia;Aplin, Andrew E.
BRAF抑制剂和MEK抑制剂的组合（BRAFi + MEKi）已被FDA批准用于治疗BRAF（V600e/K）突变黑色素瘤。BRAFi + MEKi与癌细胞死亡和肿瘤免疫微环境改变的关系然而，人们对其中的联系知之甚少。我们发现BRAFi +MEKi以免疫介导的方式引起持久的黑色素瘤消退。BRAFi + MEKi处理促进了气皮肤蛋白E （GSDME）的裂解和HMGB1的释放，HMGB1是热腐细胞死亡的标志。gsdme缺陷黑色素瘤表现为HMGB1释放缺陷，肿瘤相关T细胞减少，树突状细胞浸润活化，响应BRAFi + MEKi，药物去除后肿瘤再生更频繁。重要的是，BRAFi + meki耐药疾病缺乏焦亡标志物，肿瘤内t细胞浸润减少，但对焦亡诱导化疗敏感。这些数据暗示了BRAFi + meki诱导的焦亡在抗肿瘤免疫反应中，并强调了耐药黑色素瘤的新治疗策略。意义：靶向抑制剂和免疫检查点药物提高了黑色素瘤患者的护理水平；然而，这两个研究领域之间的交集的详细知识是缺乏的。我们描述了靶向抑制剂调控免疫刺激形式细胞死亡的分子机制，并为抑制剂耐药黑色素瘤提供了原则性的挽救治疗概念。
Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA approved to treat BRAF(V600e/K)-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi +MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi-resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi-induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.SIGNIFICANCE: Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma.