MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy
MAPK Signaling and Inflammation Link Melanoma Phenotype Switching to Induction of CD73 during Immunotherapy
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DOI：
10.1158/0008-5472.can-17-0395
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发表时间：
2017-09-01
期刊：
影响因子：
11.2
通讯作者：
Hoelzel, Michael
中科院分区：
文献类型：
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作者：
Reinhardt, Julia;Landsberg, Jennifer;Hoelzel, Michael
肿瘤细胞表型的演变促进异质性和治疗抗性。在这里，我们发现诱导CD 73，产生免疫抑制腺苷的酶，与黑色素瘤表型转换有关。活化MAPK突变和生长因子驱动CD 73表达，这标志着间充质样黑素瘤细胞状态程序的新生和完全活化。促炎细胞因子如TNF α通过c-Jun/AP-1转录因子复合物与MAPK信号传导合作，通过结合内含子增强子来激活CD 73转录。在T细胞免疫疗法的小鼠模型中，在复发性黑素瘤中诱导CD 73，其获得间充质样表型。我们还检测到在过继性T细胞转移或免疫检查点阻断下进展的黑色素瘤患者中的CD 73上调，认为这是一种适应性耐药机制。我们的工作证实了CD 73作为联合收割机与当前免疫疗法结合的靶点，但其动态调节表明CD 73预处理表达作为生物标志物对黑色素瘤患者分层的价值有限。(C)2017年AACR。
Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNF alpha cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T-cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T-cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as a target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pretreatment expression as a biomarker to stratify melanoma patients. (C) 2017 AACR.