Journal
CLINICAL CANCER RESEARCH
Volume 20, Issue 13, Pages 3446-3457Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-2797
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Funding
- NIH [P01 CA168585]
- Seaver Institute
- Dr. Robert Vigen memorial fund
- Ressler Family Foundation
- Wesley Coyle Memorial Fund
- Louise Belley and Richard Schnarr Fund
- Garcia-Corsini Family Fund
- Bila Alon Hacker Memorial Fund
- Fred L. Hartley Family Foundation
- Ruby Family Foundation
- Jonsson Cancer Center Foundation
- Caltech-UCLA Joint Center for Translational Medicine
- In Vivo Imaging in Cancer Biology (ICMIC) career development award [P50 CA086306]
- V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research
- Spanish Society of Medical Oncology (SEOM) for Translational Research in Reference Centers
- American Cancer Society [RSG-12-257-01-TBE]
- Melanoma Research Alliance [20120279]
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Purpose: PD-L1 is the main ligand for the immune inhibitory receptor PD-1. This ligand is frequently expressed by melanoma cells. In this study, we investigated whether PD-L1 expression is controlled by melanoma driver mutations and modified by oncogenic signaling inhibition. Experimental Design: Expression of PD-L1 was investigated in a panel of 51 melanoma cell lines containing different oncogenic mutations, including cell lines with innate and acquired resistance to BRAF inhibitors (BRAFi). The effects of targeted therapy drugs on expression of PD-L1 by melanoma cells were investigated. Results: No association was found between the level of PD-L1 expression and mutations in BRAF, NRAS, PTEN, or amplification of AKT. Resistance to vemurafenib due to the activation of alternative signaling pathways was accompanied with the induction of PD-L1 expression, whereas the resistance due to the reactivation of the MAPK pathway had no effect on PD-L1 expression. In melanoma cell lines, the effects of BRAF, MEK, and PI3K inhibitors on expression of PD-L1 were variable from reduction to induction, particularly in the presence of INF gamma. In PD-L1-exposed lymphocytes, vemurafenib paradoxically restored activity of the MAPK pathway and increased the secretion of cytokines. Conclusions: In melanoma cell lines, including BRAFi-resistant cells, PD-L1 expression is variably regulated by oncogenic signaling pathways. PD-L1-exposed lymphocytes decrease MAPK signaling, which is corrected by exposure to vemurafenib, providing potential benefits of combining this drug with immunotherapies. (C)2014 AACR.
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