SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy.

Journal Article (Journal Article)

UNLABELLED: The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non-small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency-induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction. SIGNIFICANCE: The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.

Full Text

Duke Authors

Cited Authors

  • Pan, D; Bao, X; Hu, M; Jiao, M; Li, F; Li, C-Y

Published Date

  • August 3, 2022

Published In

Volume / Issue

  • 82 / 15

Start / End Page

  • 2748 - 2760

PubMed ID

  • 35648422

Pubmed Central ID

  • PMC9357127

Electronic International Standard Serial Number (EISSN)

  • 1538-7445

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-21-3523


  • eng

Conference Location

  • United States