RAC1 P29S regulates PD-L1 expression in melanoma

Summary Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5–9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho‐protein expression,...

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Bibliographic Details
Published in:Pigment cell and melanoma research 2015-09, Vol.28 (5), p.590-598
Main Authors: Vu, Ha Linh, Rosenbaum, Sheera, Purwin, Timothy J., Davies, Michael A., Aplin, Andrew E.
Format: Article
Language:English
Subjects:
anti-PD-1
Antibodies
Antitumor activity
Apoptosis
B7-H1 Antigen - metabolism
Biomarkers
Cell Line, Tumor
Collagen - chemistry
Cyclin B1
Cyclin B1 - metabolism
Exome
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
immune evasion
Immune response
Immune System
Intracellular Signaling Peptides and Proteins - metabolism
MAP Kinase Kinase Kinases - metabolism
Melanoma
Melanoma - immunology
Melanoma - metabolism
Mutants
Mutation
Patients
PD-1 protein
PD-L1
PD-L1 protein
Protein arrays
Protein-Tyrosine Kinases - metabolism
Proteins
Proto-Oncogene Protein c-ets-1 - metabolism
RAC1
rac1 GTP-Binding Protein - genetics
rac1 GTP-Binding Protein - metabolism
Rac1 protein
RNA Interference
Sequence Analysis, DNA
Signal Transduction
Skin Neoplasms - immunology
Skin Neoplasms - metabolism
Syk Kinase
Syk protein
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Summary:Summary Whole exome sequencing of cutaneous melanoma has led to the detection of P29 mutations in RAC1 in 5–9% of samples, but the role of RAC1 P29 mutations in melanoma biology remains unclear. Using reverse phase protein array analysis to examine the changes in protein/phospho‐protein expression, we identified cyclin B1, PD‐L1, Ets‐1, and Syk as being selectively upregulated with RAC1 P29S expression and downregulated with RAC1 P29S depletion. Using the melanoma patient samples in TCGA, we found PD‐L1 expression to be significantly increased in RAC1 P29S patients compared to RAC1 WT as well as other RAC1 mutants. The finding that PD‐L1 is upregulated suggests that oncogenic RAC1 P29S may promote suppression of the antitumor immune response. This is a new insight into the biological function of RAC1 P29S mutations with potential clinical implications as PD‐L1 is a candidate biomarker for increased benefit from treatment with anti‐PD1 or anti‐PD‐L1 antibodies.
ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12392