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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
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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. Clin Cancer Res; 22(6); 1499–509. ©2015 AACR.
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“RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1 [213, 214].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [214]
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“trametinib promotes PD-L1 upregulation in mouse breast cancer cells, in vitro and in vivo (Loi et al., 2016)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Loi et al., 2016
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Metadata
- Authors
- Loi, S., Dushyanthen, S., Beavis, P. A., Salgado, R., Denkert, C., Savas, P., Combs, S., Rimm, D. L., Giltnane, J. M., Estrada, M. V., Sánchez, V., Sanders, M. E., Cook, R. S., Pilkinton, M. A., Mallal, S. A., Wang, K., Miller, V. A., Stephens, P. J., Yelensky, R., Doimi, F. D., Gómez, H., Ryzhov, S. V., Darcy, P. K., Arteaga, C. L., & Balko, J. M.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Institut Jules Bordet (BE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Yale University (US)
- Vanderbilt University (US)
- 7Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
- Foundation Medicine (United States) (US)
- Instituto Nacional de Enfermedades Neoplásicas (PE)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Loi, Sherene
- Balko, Justin M.
- ORCID
- Loi, Sherene
- Dushyanthen, Sathana
- Beavis, Paul A.
- Salgado, Roberto
- Denkert, Carsten
- Savas, Peter
- Rimm, David L.
- Giltnane, Jennifer M.
- Estrada, Monica V.
- Sanders, Melinda E.
- Cook, Rebecca S.
- Pilkinton, Mark A.
- Mallal, Simon A.
- Miller, Vincent A.
- Stephens, Phil J.
- Yelensky, Roman
- Doimi, Franco D.
- Gómez, Henry
- Ryzhov, Sergey V.
- Darcy, Phillip K.
- Arteaga, Carlos L.
- Balko, Justin M.
- Venue
- Clinical Cancer Research
- Published
- 2016-03-14
- Volume
- 22
- Issue
- 6
- Pages
- 1499-1509
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4794351
- OpenAlex
- W1933761723
- Cited by
- 536
- References
- 41
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 29 · 2023: 67 · 2022: 62 · 2021: 94 · 2020: 68 · 2019: 60 · 2018: 51 · 2017: 44 · 2016: 14
- FWCI
- 15.90
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-02-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- Funders
- National Institutes of Health (1k99ca181491-01a1)
- National Cancer Institute (1K99CA181491, K99 CA181491, P50CA098131, R00CA181491, P30CA068485)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- triple-negative breast cancer, tumor-infiltrating lymphocytes, RAS/MAPK pathway, MEK inhibitors, PD-1/PD-L1 inhibitors, MHC class I expression, immune evasion, combination immunotherapy, predictive biomarkers, antitumor immunity
- MeSH terms
- Animals, Disease Models, Animal, Female, Humans, Mortality, Phenotype, Signal Transduction, Biomarkers, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Disease Progression, ras Proteins, Gene Expression Profiling, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Immunomodulation, Transcriptome, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Triple Negative Breast Neoplasms
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