title: BRAFV600E Co-opts a Conserved MHC Class I Internalization Pathway to Diminish Antigen Presentation and CD8+ T-cell Recognition of Melanoma.
abstract: Oncogene activation in tumor cells induces broad and complex cellular changes that contribute significantly to disease initiation and progression. In melanoma, oncogenic BRAF(V600E) 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 BRAF(V600E) 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.
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Sherille D
authors: SD
authors: Bradley
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Zeming
authors: Z
authors: Chen
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Brenda
authors: B
authors: Melendez
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Amjad
authors: A
authors: Talukder
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jahan S
authors: JS
authors: Khalili
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Tania
authors: T
authors: Rodriguez-Cruz
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Shujuan
authors: S
authors: Liu
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Mayra
authors: M
authors: Whittington
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Wanleng
authors: W
authors: Deng
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Fenge
authors: F
authors: Li
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Chantale
authors: C
authors: Bernatchez
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Laszlo G
authors: LG
authors: Radvanyi
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Michael A
authors: MA
authors: Davies
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Patrick
authors: P
authors: Hwu
authors: Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Immunology, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas. glizee@mdanderson.org.
authors: Gregory
authors: G
authors: Lizée
mesh_terms: D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000276:immunology; D021381:Protein Transport; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015395:Histocompatibility Antigens Class I; D048493:Proto-Oncogene Proteins B-raf