title: RAC1 P29S regulates PD-L1 expression in melanoma.
abstract: 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.
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Ha Linh
authors.initials: HL
authors.lastname: Vu
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Sheera
authors.initials: S
authors.lastname: Rosenbaum
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Purwin
authors.affiliation: Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.affiliation: Department of Cancer Biology and Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.|Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Aplin
mesh_terms: D017209:Apoptosis; D060890:B7-H1 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D056744:Cyclin B1 / Q000378:metabolism; D059472:Exome; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007107:Immune System; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000378:metabolism*; D009154:Mutation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D034622:RNA Interference; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism*; D000072377:Syk Kinase; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; C534699:CCNB1 protein, human; C423236:CD274 protein, human; D056744:Cyclin B1; C494041:ETS1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050784:Proto-Oncogene Protein c-ets-1; C107953:RAC1 protein, human; D003094:Collagen; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D020930:MAP Kinase Kinase Kinases; D020830:rac1 GTP-Binding Protein
keywords: PD-L1; RAC1; anti-PD-1; immune evasion; melanoma