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Clin Cancer Res. 2016 Mar 15;22(6):1499-509. doi: 10.1158/1078-0432.CCR-15-1125. Epub 2015 Oct 29.

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.

Author information

1
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia. justin.balko@vanderbilt.edu sherene.loi@petermac.org.
2
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
3
Breast Cancer Translational Research Laboratory, Institute Jules Bordet, Brussels, Department of Pathology, GZA Antwerp, Belgium.
4
Charité University and German Cancer Consortium (DKTK), Berlin, Germany.
5
Departments of Pathology and Medicine, Yale University, New Haven, Connecticut.
6
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
7
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
8
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
9
Department of Medicine, Vanderbilt University, Nashville, Tennessee.
10
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee.
11
Foundation Medicine, Cambridge, Massachusetts.
12
Instituto Nacional de Enfermedades Neoplásicas (INEN), Lima, Perú.
13
Maine Medical Center Research Institute, Scarborough, Maine.
14
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
15
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee.
16
Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. Department of Medicine, Vanderbilt University, Nashville, Tennessee. justin.balko@vanderbilt.edu sherene.loi@petermac.org.

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.

PMID:
26515496
PMCID:
PMC4794351
DOI:
10.1158/1078-0432.CCR-15-1125
[Indexed for MEDLINE]
Free PMC Article

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