Rebecca Cook
Faculty Member
Last active: 4/15/2019

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.

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
Clin Cancer Res. 2016 22 (6): 1499-509

PMID: 26515496 · PMCID: PMC4794351 · DOI:10.1158/1078-0432.CCR-15-1125

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.

©2015 American Association for Cancer Research.

MeSH Terms (22)

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 ras Proteins Signal Transduction Transcriptome Triple Negative Breast Neoplasms

Connections (2)

This publication is referenced by other Labnodes entities:

Links