Subtyping of microsatellite stability colorectal cancer reveals guanylate binding protein 2 (GBP2) as a potential immunotherapeutic target

作者：Haizhou Wang, Yabo Zhou, Yangyang Zhang, Shilin Fang, Meng Zhang, Hai-Ou Li, Fei Xu, Lan Liu, Jing Liu, Qiu Zhao, Fan Wang · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2022 · DOI：10.1136/jitc-2021-004302 · 被引用次数：68 · 研究领域：Cancer Immunotherapy and Biomarkers、Genetic factors in colorectal cancer、Ferroptosis and cancer prognosis

BACKGROUNDS: Proficient-mismatch-repair or microsatellite stability (pMMR/MSS) colorectal cancer (CRC) has limited efficacy for immune checkpoint blockade (ICB) therapy and its underlying mechanism remains unclear. Guanylate binding protein 2 (GBP2) is a member of the GTPase family and is crucial to host immunity against pathogens. However, the correlations between GBP2 and immunosurveillance and immunotherapy for pMMR/MSS CRC have not been reported. METHODS: Unsupervised clustering was employed to classify immune class and non-immune class in 1424 pMMR/MSS patients from six independent public datasets. This binary classification was validated using immune cells or response related signatures. The correlation between GBP2 and immune microenvironment was explored using well-established biological algorithms, multiplex immunohistochemistry (mIHC), in vitro and in vivo experiments. RESULTS: We classified 1424 pMMR/MSS CRC patients into two classes, 'immune' and 'non-immune', and GBP2 was identified as a gene of interest. We found that lower GBP2 expression was correlated with poor prognosis and metastasis. GBP2 expression was also upregulated in the immune class and highly associated with interferon-γ (IFN-γ) signaling pathway and CD8 +T cell infiltration using gene set enrichment analysis, gene ontology analysis, single-cell sequencing and mIHC. Moreover, reduced GBP2 expression inhibited the antigen processing and presentation machinery and CXCL10/11 expression in MSS CRC cell...