Dana-Farber Cancer Institute - Center for Functional Cancer Epigenetics; Dana-Farber Cancer Institute - Department of Medical Oncology; Harvard University - Department of Medicine
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/ebpδ protein. Cop1 substrate Trib2 functions as a scaffold linking Cop1 and C/ebpδ, which leads to polyubiquitination of C/ebpδ. Cop1 inhibition stabilizes C/ebpδ 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.
Wang, Xiaoqing and Tokheim, Collin and Wang, Binbin and Gu, Shengqing Stan and Tang, Qin and Li, Yihao and Traugh, Nicole and Zhang, Yi and Li, Ziyi and Zhang, Boning and Fu, Jingxin and Xiao, Tengfei and Li, Wei and Meyer, Clifford A. and Jiang, Peng and Chu, Jun and Cejas, Paloma and Lim, Klothilda and Long, Henry and Brown, Myles and Liu, Xiaole Shirley, In vivo CRISPR Screens Identify E3 Ligase
Cop1 as a Modulator of Macrophage Infiltration and Cancer Immunotherapy Target. Available at SSRN: https://ssrn.com/abstract=3746625 or http://dx.doi.org/10.2139/ssrn.3746625
This version of the paper has not been formally peer reviewed.
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