Huang et al. performed an open reading frame screen of nearly 400 members of the kinase genome and an RNA-binding immunoprecipitation assay to identify the expression of RNA-binding protein MEX3B as a mechanism of tumor resistance to PD-1 blockade in melanoma. MEX3B binds to the HLA-A mRNA, leading to mRNA destabilization, downregulation of HLA-A on tumor cells, and reduced production of IFNγ by tumor-targeting T cells, thus hiding the tumor cells in plain sight and preventing T cell-mediated cytotoxicity.

PURPOSE: Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy. EXPERIMENTAL DESIGN: To identify genes mediating resistance to T cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous Tumor-Infiltrating Lymphocytes (TILs). RESULTS: The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher MEX3B expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNgamma were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' UTR of HLA-A to destabilize the mRNA. CONCLUSIONS: MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of HLA-A to destabilize the HLA-A mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells.

Author Info: (1) Melanoma, University of Texas MD Anderson Cancer Center. (2) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Department of Melanoma Medical

Author Info: (1) Melanoma, University of Texas MD Anderson Cancer Center. (2) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (3) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (4) Department of Surgical Oncology, MD Anderson Cancer Center. (5) Global Research Laboratory, Department of Biochemistry and Molecular Biology, Korea University College of Medicine. (6) University of Texas MD Anderson Cancer Center. (7) Genomic Medicine, University of Texas MD Anderson Cancer Center. (8) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (9) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (10) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (11) University of Texas MD Anderson Cancer Center. (12) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (13) Lymphoma & Myeloma, University of Texas MD Anderson Cancer Center. (14) Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center. (15) Division of Dermatology, Department of Medicine, University of California Los Angeles. (16) Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center. (17) Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. (18) Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (19) Institute for Applied Cancer Science, University of Texas MD Anderson Cancer Center. (20) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center. (21) Department of bioinformatics and computational biology, University of Texas MD Anderson Cancer Center. (22) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (23) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center. (24) Departments of Melanoma Medical Oncology and Immunology, University of Texas MD Anderson Cancer Center. (25) Department of Systems Biology, University of Texas MD Anderson Cancer Center. (26) Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center phwu@mdanderson.org.

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