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Updated: Apr 30, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Effects of MAPK and PI3K pathways on PD-L1 expression in melanoma
Mohammad Atefi1, Earl Avramis1, Amanda Lassen1
1Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine;
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 INFγ. 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.
Insights
Melanoma cell PD-L1 expression is variably controlled by oncogenic pathways, even in BRAF inhibitor-resistant cells. Vemurafenib may benefit combination immunotherapy by restoring T-cell activity.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed cell death ligand 1 (PD-L1) is a key immune checkpoint target.
- PD-L1 is frequently expressed on melanoma cells, contributing to immune evasion.
- Understanding PD-L1 regulation in melanoma is crucial for effective cancer immunotherapy.
Purpose of the Study:
- To investigate the role of melanoma driver mutations in regulating PD-L1 expression.
- To determine how oncogenic signaling inhibition affects PD-L1 levels in melanoma.
- To explore the impact of BRAF inhibitors (BRAFi) on PD-L1 expression in resistant melanoma models.
Main Methods:
- Analyzed PD-L1 expression in 51 melanoma cell lines with diverse mutations.
- Assessed effects of targeted therapy drugs (BRAF, MEK, PI3K inhibitors) on PD-L1.
- Investigated PD-L1 regulation in melanoma with innate and acquired BRAFi resistance.
Main Results:
- No correlation found between PD-L1 levels and mutations in BRAF, NRAS, PTEN, or AKT amplification.
- Acquired resistance to vemurafenib via alternative pathways induced PD-L1; MAPK reactivation did not.
- BRAF, MEK, and PI3K inhibitors showed variable effects on PD-L1, influenced by INFγ.
Conclusions:
- Melanoma PD-L1 expression is variably modulated by oncogenic signaling, including in BRAFi-resistant contexts.
- Vemurafenib restored MAPK signaling in PD-L1-exposed lymphocytes, suggesting potential for combination therapy.
- Targeted therapy combined with immunotherapy may offer synergistic benefits in melanoma treatment.
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