Dajiang Guo

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.

Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.