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

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 (TIL). 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 expression 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' untranslated region (UTR) of to destabilize the mRNA. MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of to destabilize the 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. .

The RNA‐binding protein SORBS2 suppresses hepatocellular carcinoma tumourigenesis and metastasis by stabilizing RORA mRNA

“…32 In melanoma, Huang et al identified that MEX3B decreased the susceptibility of cancer immunotherapy by targeting HLA-A. 33 Therefore, exploring the precise roles of In summary, this study first characterized the frequent downregulation of SORBS2 in HCC and showed the antitumour function of SORBS2 on the malignant phenotypes of HCC cells, including cell proliferation, migration, invasion, cell cycle progression and EMT both in vitro and in vivo. We further elucidated the underlying molecular mechanism by which SORBS2 stabilized RORA mRNA by binding with its 3′UTR.…”

“…Chen et al showed that ROD1 regulated transcription and was required for defining AID‐loading sites to mediate antibody class switching with a PTBP3 deletion in mammalian genomes . In melanoma, Huang et al identified that MEX3B decreased the susceptibility of cancer immunotherapy by targeting HLA‐A . Therefore, exploring the precise roles of SORBS2 during HCC tumourigenesis may help to open novel avenues for the pathogenesis and treatment of HCC.…”

Perspectives in melanoma: meeting report from the “Melanoma Bridge” (December 5th–7th, 2019, Naples, Italy)

“…RNA-binding protein MEX3B was identified as a candidate protein whose overexpression in melanoma cells decreased their susceptibility to killing by autologous TIL in vitro suggesting that it mediates resistance to cancer immunotherapy. Overexpression of MEX3B in melanoma cells decreased IFN-γ release by autologous TILs and downregulated HLA-A expression [32]. Downregulation of HLA-A expression by MEX3B is a novel mechanism for tumor cells to evade attack by T cells.…”

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

“…HLA class I loss has been shown to prevent continuous T cell recognition in a human melanoma model [154]. HLA-A down-regulation is mediated e.g., by the RNA-binding protein MEX3B [155], by loss of function mutations in the genes encoding the interferon-receptor associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2) [156][157][158] or by truncating mutations in the gene encoding β2m [156]. A major impact of HLA class I genotype on clinical outcome with ICI has been corroborated by Chowell et al HLA-I homozygosity in at least one locus was associated with an inferior survival in two independent cancer cohorts undergoing immune-checkpoint blockade and proved as an independent predictor of survival in multivariate analysis.…”