关键词： 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 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

来  源：   DOI：10.1016/j.apsb.2021.08.006   PDF(Sci-hub)   PDF(Pubmed)

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.
摘要：
结直肠癌(CRC),世界范围内的恶性肿瘤由微卫星不稳定性（MSI）和稳定（MSS）表型组成。尽管SHP2是癌症治疗的一个有希望的靶点，它与先天免疫抑制的关系仍然难以捉摸。为了解决这个问题，进行单细胞RNA测序以探索SHP2在小鼠MC38异种移植物的所有细胞类型的肿瘤微环境（TME）中的作用。发现瘤内细胞在功能上是异质的，并且对SHP2变构抑制剂SHP099有显着反应。SHP099明显阻止了肿瘤细胞的恶性演变。机械上,STING-TBK1-IRF3介导的I型干扰素信号在浸润的骨髓细胞中被SHP099高度激活。值得注意的是,与MSI高表型相比，具有MSS表型的CRC患者在CD68巨噬细胞中表现出更大的巨噬细胞浸润和更有效的SHP2磷酸化，提示巨噬细胞SHP2在TME中的潜在作用。总的来说，我们的数据揭示了SHP2介导的先天免疫抑制机制,提示SHP2是结肠癌免疫治疗的一个有前景的靶点.
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