MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma

Cancer Res. 2021 Aug 15;81(16):4242-4256. doi: 10.1158/0008-5472.CAN-21-1677. Epub 2021 Jun 18.

Abstract

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. SIGNIFICANCE: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism*
  • Animals
  • Biological Transport
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Nucleus / metabolism
  • Gene Deletion
  • HEK293 Cells
  • Humans
  • Immune Evasion*
  • Immune System
  • Introns
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Nude
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism*
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA, Double-Stranded*
  • Sequence Analysis, DNA
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Kruppel-Like Transcription Factors
  • Proto-Oncogene Proteins c-myc
  • RNA, Double-Stranded
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • ZBTB17 protein, human
  • Tbk1 protein, mouse
  • Protein Serine-Threonine Kinases