RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors.
RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors.
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DOI：
10.1158/1078-0432.ccr-15-1125
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发表时间：
2016-03-15
期刊：
影响因子：
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通讯作者：
Balko JM
中科院分区：
文献类型：
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作者：
Loi S;Dushyanthen S;Beavis PA;Salgado R;Denkert C;Savas P;Combs S;Rimm DL;Giltnane JM;Estrada MV;Sánchez V;Sanders ME;Cook RS;Pilkinton MA;Mallal SA;Wang K;Miller VA;Stephens PJ;Yelensky R;Doimi FD;Gómez H;Ryzhov SV;Darcy PK;Arteaga CL;Balko JM
新辅助化疗（NAC）后三阴性乳腺癌（TNBC）残留病变（RD）中的肿瘤浸润淋巴细胞（TIL）与生存率改善相关，但缺乏对影响这些特征的肿瘤细胞自主分子途径的了解。我们分析了NAC后临床和分子表征的TNBC RD中的TIL，并在乳腺癌小鼠模型中探索了靶向MEK抑制剂与PD-1/PD-L1靶向免疫疗法组合的治疗策略。RD中存在TIL与预后改善显著相关。Ras/MAPK信号的遗传或转录组学改变与较低的TIL显著相关。MEK抑制在体内和体外均上调TNBC细胞中的细胞表面主要组织相容性复合物（MHC）表达和PD-L1。此外，组合的MEK和PDL-1/PD-1抑制增强了乳腺癌小鼠模型中的抗肿瘤免疫应答。这些数据表明Ras/MAPK通路活化促进TNBC中的免疫逃避的可能性，并支持结合MEK和PD-L1靶向疗法的临床试验。此外，Ras/MAPK活化和MHC表达可能是对免疫检查点抑制剂应答的预测性生物标志物。
Tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) of triple-negative breast cancers (TNBCs) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1-targeted immunotherapy in mouse models of breast cancer. Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras/MAPK signaling were significantly correlated with lower TILs. MEK inhibition up-regulated cell-surface major histocompatibility complex (MHC) expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PDL-1/PD-1 inhibition enhanced anti-tumor immune responses in mouse models of breast cancer. These data suggest the possibility that Ras/MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.