In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target.
In vivo CRISPR screens identify the E3 ligase Cop1 as a modulator of macrophage infiltration and cancer immunotherapy target.
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DOI：
10.1016/j.cell.2021.09.006
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发表时间：
2021-10-14
期刊：
影响因子：
64.5
通讯作者：
Liu, X. Shirley
中科院分区：
文献类型：
--
作者：
Wang, Xiaoqing;Tokheim, Collin;Gu, Shengqing Stan;Wang, Binbin;Tang, Qin;Li, Yihao;Traugh, Nicole;Zeng, Zexian;Zhang, Yi;Li, Ziyi;Zhang, Boning;Fu, Jingxin;Xiao, Tengfei;Li, Wei;Meyer, Clifford A.;Chu, Jun;Jiang, Peng;Cejas, Paloma;Lim, Klothilda;Long, Henry;Brown, Myles;Liu, X. Shirley
尽管免疫检查点阻断(ICB)在癌症治疗中的临床疗效显著，但ICB在三阴性乳腺癌(TNBC)中的益处仍然有限。通过在同基因的TNBC小鼠模型体内混合CRISPR基因敲除(KO)筛选，我们发现癌细胞中E3泛素连接酶Cop1的缺失减少了巨噬细胞相关趋化因子的分泌，减少了肿瘤巨噬细胞的侵袭，增强了抗肿瘤免疫，并增强了ICB反应。转录组学、表观基因组学和蛋白质组学分析表明，Cop1通过蛋白酶体降解C/eBPδ蛋白发挥作用。CoP 1底物Trib2作为连接CoP 1和C/eBPδ的支架，导致C/eBPδ的多泛素化。此外，癌细胞中E3泛素连接酶COP1的缺失可以稳定C/eBPδ，从而抑制巨噬细胞趋化基因的表达。我们的综合方法表明，通过调节肿瘤微环境中趋化因子的分泌和巨噬细胞的渗透，Cop1可作为提高TNBC肿瘤免疫治疗效果的靶点。大规模体内CRISPR筛选显示，肿瘤细胞中的Cop1基因敲除稳定了C/eBPδ蛋白，从而抑制了巨噬细胞的侵袭，增强了抗肿瘤免疫。
Despite remarkable clinical efficacy 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 deletion of the E3 ubiquitin ligase Cop1 in cancer cells decreases the secretion of macrophage-associated chemokines, reduces tumor macrophage infiltration, enhances anti-tumor immunity, and strengthens ICB response. Transcriptomics, epigenomics, and proteomics analyses revealed that 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. In addition, deletion of the E3 ubiquitin ligase Cop1 in cancer cells stabilizes C/ebpδ to suppress the expression of macrophage chemoattractant genes. Our integrated approach implicates Cop1 as a target for improving cancer immunotherapy efficacy in TNBC by regulating chemokine secretion and macrophage infiltration in the tumor microenvironment. Large-scale in vivo CRISPR screens reveal that Cop1 knockout in cancer cells stabilizes C/ebpδ protein, thereby suppressing macrophage infiltration and enhancing anti-tumor immunity.
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影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
32.4
作者：
Dersh D;Phelan JD;Gumina ME;Wang B;Arbuckle JH;Holly J;Kishton RJ;Markowitz TE;Seedhom MO;Fridlyand N;Wright GW;Huang DW;Ceribelli M;Thomas CJ;Lack JB;Restifo NP;Kristie TM;Staudt LM;Yewdell JW
通讯作者：
Yewdell JW
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
64.8
作者：
Dornan, D;Wertz, I;Dixit, VM
通讯作者：
Dixit, VM
影响因子：
5.8
作者：
Alshaker HA;Matalka KZ
通讯作者：
Matalka KZ