Title |
The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression
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Published in |
Clinical Cancer Research, July 2018
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DOI | 10.1158/1078-0432.ccr-17-2483 |
Pubmed ID | |
Authors |
Lu Huang, Shruti Malu, Jodi A. McKenzie, Miles C. Andrews, Amjad H. Talukder, Trang Tieu, Tatiana Karpinets, Cara Haymaker, Marie-Andrée Forget, Leila J. Williams, Zhe Wang, Rina M. Mbofung, Zhi-Qiang Wang, Richard Eric Davis, Roger S. Lo, Jennifer A. Wargo, Michael A. Davies, Chantale Bernatchez, Timothy Heffernan, Rodabe N. Amaria, Anil Korkut, Weiyi Peng, Jason Roszik, Gregory Lizée, Scott E. Woodman, Patrick Hwu |
Abstract |
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. 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). 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 higherMEX3Bexpression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ 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 ofHLA-Ato destabilize the mRNA. MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR ofHLA-Ato destabilize theHLA-AmRNA 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 4 | 36% |
Colombia | 1 | 9% |
Italy | 1 | 9% |
United Kingdom | 1 | 9% |
Unknown | 4 | 36% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 9 | 82% |
Scientists | 1 | 9% |
Science communicators (journalists, bloggers, editors) | 1 | 9% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 80 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 14 | 18% |
Researcher | 12 | 15% |
Student > Bachelor | 9 | 11% |
Other | 7 | 9% |
Student > Master | 6 | 8% |
Other | 10 | 13% |
Unknown | 22 | 28% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 21 | 26% |
Medicine and Dentistry | 15 | 19% |
Immunology and Microbiology | 7 | 9% |
Agricultural and Biological Sciences | 6 | 8% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 3% |
Other | 8 | 10% |
Unknown | 21 | 26% |