Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics

查看全文 作　　者：Jian [1]Gao;Zhigui [1]Wu;Mingxia [1,2]Zhao;Rui [3]Zhang;Manru [1]Li;Dongdong [4]Sun;Haibo [4]Cheng;Xianjia [5]Qi;Yuxian [2]Shen;Qiang [1,6]Xu;Hongqi [7]Chen;Dijun [1]Chen;Yang [1,6]Sun

机构地区：[1]State Key Laboratory of Pharmaceutical Biotechnology,Chemistry and Biomedicine Innovation Center(Chem BIC),School of Life Sciences,Nanjing University,Nanjin 210023,China;[2]Biopharmaceutical Research Institute,School of Basic Medical Sciences,Anhui Medical University,Hefei 230032,China;[3]Department of Colorectal Surgery,Cancer Hospital of China Medical University,Liaoning Cancer Hospital&Institute,Shenyang 110042,China;[4]The First Clinical College of Nanjing University of Chinese Medicine,Nanjing 210023,China;[5]Shanghai Xu Ran Biotechnology Co.,Ltd.,Shanghai 201109,China;[6]Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou Medical University,Xuzhou 221004,China;[7]Department of General Surgery,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,Shanghai 200233,China

出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第1期,共18页

基　　金：supported by National Natural Science Foundation of China(Nos.91853109,81730100,81872877,and 81673436);Mountain-Climbing Talents Project of Nanjing University(China)。 摘　　要：Colorectal cancer(CRC), a malignant tumor worldwide consists of microsatellite instability(MSI) and stable(MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing wasperformed to explore the role of SHP2 in all cell types of tumor microenvironment(TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68;macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively,our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy. 关键词：Tumor microenvironment PTPN11 SHP099 STING Type I interferon Colorectal cancer scRNA-seq Macrophage

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Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics

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