The SETDB1-TRIM28 Complex Suppresses Antitumor Immunity. Academic Article uri icon

Overview

abstract

  • The tumor immune microenvironment is influenced by the epigenetic landscape of the tumor. Here, we have identified the SETDB1-TRIM28 complex as a critical suppressor of antitumor immunity. An epigenetic CRISPR-Cas9 screen of 1,218 chromatin regulators identified TRIM28 as a suppressor of PD-L1 expression. We then revealed that expression of the SETDB1-TRIM28 complex negatively correlated with infiltration of effector CD8+ T cells. Inhibition of SETDB1-TRIM28 simultaneously upregulated PD-L1 and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway to increase infiltration of CD8+ T cells. Mechanistically, SETDB1-TRIM28 inhibition led to micronuclei formation in the cytoplasm, which is known to activate the cGAS-STING pathway. Thus, SETDB1-TRIM28 inhibition bridges innate and adaptive immunity. Indeed, SETDB1 knockout enhanced the antitumor effects of immune checkpoint blockade with anti-PD-L1 in a mouse model of ovarian cancer in a cGAS-dependent manner. Our findings establish the SETDB1-TRIM28 complex as a regulator of antitumor immunity and demonstrate that its loss activates cGAS-STING innate immunity to boost the antitumor effects of immune checkpoint blockade.

publication date

  • December 1, 2021

Research

keywords

  • Epigenomics
  • Histone-Lysine N-Methyltransferase
  • Immunity, Innate
  • Immunotherapy
  • Ovarian Neoplasms
  • Tripartite Motif-Containing Protein 28

Identity

PubMed Central ID

  • PMC8647838

Scopus Document Identifier

  • 85121972916

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-21-0754

PubMed ID

  • 34848497

Additional Document Info

volume

  • 9

issue

  • 12