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The RNA-binding Protein MEX3B Mediates Resistance to Cancer Immunotherapy by Downregulating HLA-A Expression

Lu Huang1, Shruti Malu1, Jodi A McKenzie1

  • 1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 3, 2018
PubMed

Insights

MEX3B protein confers resistance to cancer immunotherapy by reducing tumor cell recognition by T cells. It achieves this by decreasing HLA-A expression, a key molecule for T cell-mediated killing.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Cancer immunotherapy offers clinical benefits but faces resistance in some patients.
  • Novel strategies are needed to overcome immunotherapy resistance.
  • Understanding resistance mechanisms is crucial for improving treatment efficacy.

Purpose of the Study:

  • Identify genes conferring resistance to cancer immunotherapy.
  • Elucidate the mechanisms by which these genes mediate resistance.
  • Investigate the role of RNA-binding proteins in immunotherapy resistance.

Main Methods:

  • Performed an open reading frame (ORF) screen using a kinome library to identify resistance genes.
  • Utilized patient-derived melanoma cells and autologous tumor-infiltrating lymphocytes (TILs).
  • Analyzed patient tumor samples treated with anti-PD-1 therapy and performed molecular assays (luciferase, RIP).

Main Results:

  • Identified MEX3B, an RNA-binding protein, as a mediator of resistance to TIL-mediated killing.
  • Found higher MEX3B expression associated with resistance to PD-1 blockade in melanoma patients.
  • Demonstrated that MEX3B downregulates HLA-A expression by destabilizing HLA-A mRNA, impairing T cell recognition.

Conclusions:

  • MEX3B confers resistance to cancer immunotherapy by downregulating surface HLA-A expression.
  • This downregulation occurs through MEX3B binding to the 3' UTR of HLA-A mRNA, leading to its destabilization.
  • Targeting MEX3B may represent a strategy to enhance the effectiveness of cancer immunotherapy.

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