Title

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.

Document Type

Article

Publication Date

3-15-2016

Institution/Department

Maine Medical Center Research Institute

Journal Title

Clinical cancer research : an official journal of the American Association for Cancer Research

MeSH Headings

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

ISSN

1078-0432

Abstract

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.

First Page

1499

Last Page

1509

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