SETDB1-TRIM28 complex suppresses antitumor immunity [CRISPR/Cas9 screen]

Epigenetic mechanism contributes to immune landscapes in cancer. Here we identify 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 novel suppressor of PD-L1 expression. We revealed that expression of the SETDB1-TRIM28 complex negatively correlates with infiltration of effector CD8+ T cells. Inhibition of SETDB1-TRIM28 simultaneously upregulates PD-L1 and activates the cGAS-STING innate immune response to increase infiltration of CD8+ T cells. Mechanistically, SETDB1-TRIM28 inhibition leads to micronuclei formation in cytoplasm, a known activator of the cGAS-STING pathway. Thus, SETDB1-TRIM28 inhibition bridges the innate and adaptive immunity. Indeed, SETDB1 knockout enhances the antitumor effects of immune checkpoint blockade anti-PD-L1 in an ovarian cancer mouse model in a cGAS dependent manner. Our findings establish SETDB1-TRIM28 complex as a regulator of antitumor immunity and its loss activates cGAS-STING innate immunity to boost antitumor effects of immune checkpoint blockades. Epigenetic CRISPR/Cas9 screen

表观遗传机制（epigenetic mechanism）参与调控癌症的免疫图谱（immune landscapes）。本研究鉴定出SETDB1-TRIM28复合物（SETDB1-TRIM28 complex）是抗肿瘤免疫（antitumor immunity）的关键抑制因子。通过对1218个染色质调控因子（chromatin regulators）开展表观遗传CRISPR-Cas9筛选（epigenetic CRISPR-Cas9 screen），我们发现TRIM28是PD-L1（Programmed Death-Ligand 1）表达的新型抑制因子。研究显示，SETDB1-TRIM28复合物的表达水平与效应性CD8+ T细胞（effector CD8+ T cells）的浸润呈负相关。抑制SETDB1-TRIM28可同时上调PD-L1的表达，并激活cGAS-STING天然免疫应答（cGAS-STING innate immune response），从而促进CD8+ T细胞的浸润。从机制层面而言，抑制SETDB1-TRIM28会导致细胞质（cytoplasm）中形成微核（micronuclei formation），而微核是已知的cGAS-STING通路激活剂。因此，抑制SETDB1-TRIM28可实现天然免疫与适应性免疫（adaptive immunity）的衔接。实验证实，在卵巢癌小鼠模型（ovarian cancer mouse model）中，SETDB1基因敲除（SETDB1 knockout）可通过cGAS依赖的方式增强抗PD-L1免疫检查点阻断剂（immune checkpoint blockade anti-PD-L1）的抗肿瘤效果。本研究确立了SETDB1-TRIM28复合物作为抗肿瘤免疫调控因子的地位，其缺失可激活cGAS-STING天然免疫，进而增强免疫检查点阻断剂的抗肿瘤功效。表观遗传CRISPR/Cas9筛选