Loi Sherene, Dushyanthen Sathana, Beavis Paul A, Salgado Roberto, Denkert Carsten, Savas Peter, Combs Susan, Rimm David L, Giltnane Jennifer M, Estrada Monica V, Sánchez Violeta, Sanders Melinda E, Cook Rebecca S, Pilkinton Mark A, Mallal Simon A, Wang Kai, Miller Vincent A, Stephens Phil J, Yelensky Roman, Doimi Franco D, Gómez Henry, Ryzhov Sergey V, Darcy Phillip K, Arteaga Carlos L, Balko Justin M
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Clin Cancer Res. 2016 Mar 15;22(6):1499-509. doi: 10.1158/1078-0432.CCR-15-1125. Epub 2015 Oct 29.
Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) 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 upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor 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.
新辅助化疗（NAC）后三阴性乳腺癌（TNBC）残留病灶（RD）中的肿瘤浸润淋巴细胞（TIL）与生存率提高相关，但对于影响这些特征的肿瘤细胞自主分子途径仍缺乏深入了解。
我们分析了NAC后临床和分子特征明确的TNBC的RD中的TIL，并在乳腺癌小鼠模型中探索了针对MEK抑制剂与PD-1/PD-L1靶向免疫疗法联合使用的治疗策略。
RD中TIL的存在与预后改善显著相关。Ras-MAPK信号通路中的基因或转录组改变与较低的TIL显著相关。MEK抑制在体内和体外均上调了TNBC细胞表面的MHC表达和PD-L1。此外，MEK和PD-L1/PD-1联合抑制增强了乳腺癌小鼠模型中的抗肿瘤免疫反应。
这些数据表明Ras-MAPK途径激活可能促进TNBC的免疫逃逸，并支持将MEK和PD-L1靶向疗法联合使用的临床试验。此外，Ras/MAPK激活和MHC表达可能是免疫检查点抑制剂反应的预测生物标志物。
