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In Vivo CRISPR Screens Identify E3 Ligase Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target

By Xiaoqing Wang, Collin Tokheim, Binbin Wang, Shengqing Gu, Qin Tang, Yihao Li, Nicole Traugh, Yi Zhang, Ziyi W Li, Boning Zhang, Jingxin Fu, Tengfei Xiao, Wei Li, Clifford A. Meyer, Jun Chu, Peng Jiang, Paloma Cejas, Klothilda Lim, Henry W Long, Myles Brown, Xiaole Shirley Liu

Posted 10 Dec 2020
bioRxiv DOI: 10.1101/2020.12.09.418012

Despite remarkable clinical efficacies of immune checkpoint blockade (ICB) in cancer treatment, ICB benefits in triple-negative breast cancer (TNBC) remain limited. Through pooled in vivo CRISPR knockout (KO) screens in syngeneic TNBC mouse models, we found that inhibition of the E3 ubiquitin ligase Cop1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, and shows synergy in anti-tumor immunity with ICB. Transcriptomics, epigenomics, and proteomics analyses revealed Cop1 functions through proteasomal degradation of the C/ebp{delta} protein. Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebp{delta}, which leads to polyubiquitination of C/ebp{delta}. Cop1 inhibition stabilizes C/ebp{delta} to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy by regulating chemokine secretion and macrophage levels in the TNBC tumor microenvironment.

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