Journal article
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
Clinical Cancer Research, Vol.22(6), pp.1499-1509
2016
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.
Details
- 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
- Authors/Creators
- S. Loi (Author/Creator)S. Dushyanthen (Author/Creator)P.A. Beavis (Author/Creator)R. Salgado (Author/Creator)C. Denkert (Author/Creator)P. Savas (Author/Creator)S. Combs (Author/Creator)D.L. Rimm (Author/Creator)J.M. Giltnane (Author/Creator)M.V. Estrada (Author/Creator)V. Sanchez (Author/Creator)M.E. Sanders (Author/Creator)R.S. Cook (Author/Creator)M.A. Pilkinton (Author/Creator)S.A. Mallal (Author/Creator)K. Wang (Author/Creator)V. A. Miller (Author/Creator)P.J. Stephens (Author/Creator)R. Yelensky (Author/Creator)F.D. Doimi (Author/Creator)H. Gomez (Author/Creator)S.V. Ryzhov (Author/Creator)P.K. Darcy (Author/Creator)C.L. Arteaga (Author/Creator)J.M. Balko (Author/Creator)
- Publication Details
- Clinical Cancer Research, Vol.22(6), pp.1499-1509
- Publisher
- American Association for Cancer research
- Identifiers
- 991005543817407891
- Copyright
- © 2015 American Association for Cancer Research
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
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- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.214 Checkpoint Inhibition
- Web Of Science research areas
- Oncology
- ESI research areas
- Clinical Medicine