RT Journal Article
SR Electronic
T1 BRAF<sup>V600E</sup> Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8<sup>+</sup> T-cell Recognition of Melanoma
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 602
OP 609
DO 10.1158/2326-6066.CIR-15-0030
VO 3
IS 6
A1 Bradley, Sherille D.
A1 Chen, Zeming
A1 Melendez, Brenda
A1 Talukder, Amjad
A1 Khalili, Jahan S.
A1 Rodriguez-Cruz, Tania
A1 Liu, Shujuan
A1 Whittington, Mayra
A1 Deng, Wanleng
A1 Li, Fenge
A1 Bernatchez, Chantale
A1 Radvanyi, Laszlo G.
A1 Davies, Michael A.
A1 Hwu, Patrick
A1 Lizée, Gregory
YR 2015
UL http://cancerimmunolres.aacrjournals.org/content/3/6/602.abstract
AB Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAFV600E has been shown to drive the transcription of a specific gene signature that can promote multiple mechanisms of immune suppression within the tumor microenvironment. We show here that BRAFV600E also induces rapid internalization of MHC class I (MHC-I) from the melanoma cell surface and its intracellular sequestration within endolysosomal compartments. Importantly, MAPK inhibitor treatment quickly restored MHC-I surface expression in tumor cells, thereby enhancing melanoma antigen-specific T-cell recognition and effector function. MAPK pathway–driven relocalization of HLA-A*0201 required a highly conserved cytoplasmic serine phosphorylation site previously implicated in rapid MHC-I internalization and recycling by activated immune cells. Collectively, these data suggest that oncogenic activation of BRAF allows tumor cells to co-opt an evolutionarily conserved MHC-I trafficking pathway as a strategy to facilitate immune evasion. This link between MAPK pathway activation and the MHC-I cytoplasmic tail has direct implications for immunologic recognition of tumor cells and provides further evidence to support testing therapeutic strategies combining MAPK pathway inhibition with immunotherapies in the clinical setting. Cancer Immunol Res; 3(6); 602–9. ©2015 AACR.