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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

par Loi, Sherene ;Estrada, Mónica Valeria;Sanchez, Violeta;Sanders, Melinda M.E.;Cook, Rebecca R.S.;Pilkinton, Mark Alexander Lexander M.A.;Mallal, Simon Alexander;Wang, Kai;Miller, Vincent A;Stephens, Philip J;Yelensky, Roman;Dushyanthen, Sathana;Doimi, Franco F.D.;Gomez, Henry;Ryzhov, Sergey S.V.;Darcy, Phillip K;Arteaga, Carlos C.L.;Balko, Justin J.M.;Beavis, Paul P.A.;Salgado, Roberto;Denkert, Carsten;Savas, Peter;Combs, Susan;Rimm, David D.L.;Giltnane, Jennifer J.M.
Référence Clinical cancer research, 22, 6, page (1499-1509)
Publication Publié, 2016-03

Article révisé par les pairs

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Résumé :

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: These data suggest the possibility that Ras-MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PDL1-targeted therapies. Furthermore, Ras/MAPK activation andMHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499-509.