Tumor Cell-Intrinsic E3 Ligase TRIM21 Restrains Radiation-Induced Antitumor Immunity by Decreasing Mitochondrial DNA Release from VDAC2 Oligomers

Abstract

<h3>Purpose/Objective(s)</h3> Radiotherapy has been proved to activate antitumor immunity but how aberrantly expressed genes in cancer regulated this process remains elusive. <h3>Materials/Methods</h3> We identified TRIM21, an E3 ligase gene, by bioinformatics analysis based on gross sequencing and single-cell sequencing data of nasopharyngeal carcinoma (NPC). The impact of TRIM21on radiation-induced antitumor immune response was identified in vitro and in vivo by TRIM21 knockout. We also determined the prognosis value of TRIM21 in NPC tissues with immunohistochemical analysis. <h3>Results</h3> Tumor cell-intrinsic E3 ligase tripartite motif-containing 21(TRIM21) is inversely associated with CD8+ T cell antitumor immunity and radiation response in NPC. Knockout of TRIM21 promoted radiation-induced antigen presentation, chemokine expression, dendritic cells, and CD8+ T cells activation in vitro, and led to enhanced radiation efficacy and immune response in MC38 murine colon adenocarcinoma, and transplanted NPC tumor in humanized mice in vivo. In mechanism, knockout of TRIM21 reversed its degradation of mitochondrial voltage-dependent anion-selective channel protein 2 (VDAC2), which resulted in sufficient VDAC2 oligomerization, mitochondrial DNA release, and thus strengthened activation of STING and type I interferon signaling during radiation. Clinically, high expression of TRIM21 in NPC indicated poor prognosis and tumor relapse after radiation. <h3>Conclusion</h3> Tumor cell-intrinsic TRIM21 suppressed radiation-induced antitumor immunity and predicted poor survival in NPC patients.