The SETDB1-TRIM28 complex suppresses antitumor immunity Journal Article


Authors: Lin, J.; Guo, D.; Liu, H.; Zhou, W.; Wang, C.; Müller, I.; Kossenkov, A. V.; Drapkin, R.; Bitler, B. G.; Helin, K.; Zhang, R.
Article Title: The SETDB1-TRIM28 complex suppresses antitumor immunity
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.
Keywords: survival; methyltransferase; histone h3; expression; ovarian-cancer; cells; pd-l1; kap1; setdb1; 2nd-messenger
Journal Title: Cancer Immunology Research
Volume: 9
Issue: 12
ISSN: 2326-6066
Publisher: American Association for Cancer Research  
Date Published: 2021-12-01
Start Page: 1413
End Page: 1424
Language: English
ACCESSION: WOS:000727264200001
DOI: 10.1158/2326-6066.Cir-21-0754
PROVIDER: wos
PMCID: PMC8647838
PUBMED: 34848497
Notes: Article -- Source: Wos
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  1. Kristian Helin
    35 Helin
  2. Iris Muller
    4 Muller