Allosteric inhibition reveals SHP2-mediated tumor immunosuppression in colon cancer by single-cell transcriptomics.
10.1016/j.apsb.2021.08.006
- Author:
Jian GAO
1
;
Zhigui WU
1
;
Mingxia ZHAO
1
;
Rui ZHANG
2
;
Manru LI
1
;
Dongdong SUN
3
;
Haibo CHENG
3
;
Xianjia QI
4
;
Yuxian SHEN
5
;
Qiang XU
1
;
Hongqi CHEN
6
;
Dijun CHEN
1
;
Yang SUN
1
Author Information
1. State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Life Sciences, Nanjing University, Nanjing 210023, China.
2. Department of Colorectal Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
3. The First Clinical College of Nanjing University of Chinese Medicine, Nanjing 210023, China.
4. Shanghai XuRan Biotechnology Co., Ltd., Shanghai 201109, China.
5. Biopharmaceutical Research Institute, School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China.
6. Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
- Publication Type:Journal Article
- Keywords:
APC, antigen-presenting cell;
BTLA, B- and T-lymphocyte attenuator;
CNVs, copy number variations;
CRC, colorectal cancer;
Colorectal cancer;
DSBs, double-strand breaks;
GSEA, gene set enrichment analysis;
KRAS, Kirsten rat sarcoma viral oncogene homolog;
MAPK, mitogen-activated kinase;
MSI, microsatellite instability;
MSS, microsatellite stable;
Macrophage;
PCA, principal component analysis;
PD-1, programmed cell death 1;
PTPN11;
SHP099;
STING;
STING, stimulator of interferon genes;
TME, tumor microenvironment;
Tumor microenvironment;
Type I interferon;
scRNA-seq;
scRNA-seq, single-cell RNA-sequencing;
t-SNE, t-distributed stochastic neighbor embedding
- From:
Acta Pharmaceutica Sinica B
2022;12(1):149-166
- CountryChina
- Language:English
-
Abstract:
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 was performed 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.
