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.
Maine Medical Center Research Institute
Clinical cancer research : an official journal of the American Association for Cancer Research
Animals, B7-H1 Antigen, Biomarkers, Cell Line, Tumor, Disease Models, Animal, Disease Progression, Female, Gene Expression Profiling, Humans, Immunomodulation, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Mice, Mitogen-Activated Protein Kinases, Mortality, Phenotype, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Signal Transduction, Transcriptome, Triple Negative Breast Neoplasms, ras Proteins
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 PD-L1-targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors.
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; and Balko, Justin M, "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." (2016). Maine Medical Center. 795.