mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers

作者：Lei Cheng, Yanan Wang, Li‐Xin Qiu, Yuanyuan Chang, Haijiao Lu, Chenchen Liu, Bo Zhang, Yan Zhou, Hao Bai, Liwen Xiong, Hua Zhong, Wei Nie, Baohui Han · 发表于：Journal of Translational Medicine · 年份：2022 · DOI：10.1186/s12967-022-03436-1 · 被引用次数：17 · 研究领域：Cancer Immunotherapy and Biomarkers、Renal cell carcinoma treatment、PI3K/AKT/mTOR signaling in cancer

BACKGROUND: mTOR pathway is known to promote cancer malignancy and influence cancer immunity but is unknown for its role in immune checkpoint inhibitors (ICI) therapy. METHODS: Using Memorial Sloan-Kettering Cancer Center dataset (MSKCC), we extracted mTOR pathway gene mutations for stepwise Cox regression in 1661 cancer patients received ICI. We associated the mutation of the gene signature resulted from the stepwise Cox regression with the 1661 patients' survival. Other 553 ICI-treated patients were collected from 6 cohorts for validation. We also performed this survival association in patients without ICI treatment from MSKCC as discovery (n = 2244) and The Cancer Genome Atlas (TCGA) as validation (n = 763). Pathway enrichment analysis were performed using transcriptome profiles from TCGA and IMvigor210 trial to investigate the potential mechanism. RESULTS: We identified 8 genes involved in mTOR pathway, including FGFR2, PIK3C3, FGFR4, FGFR1, FGF3, AKT1, mTOR, and RPTOR, resulted from stepwise Cox regression in discovery (n = 1661). In both discovery (n = 1661) and validation (n = 553), the mutation of the 8-gene signature was associated with better survival of the patients treated with ICI, which was independent of tumor mutation burden (TMB) and mainly attributed to the missense mutations. This survival association was not observed in patients without ICI therapy. Intriguingly, the mutation of the 8-gene signature was associated with increased TMB and PD1/PD-L1 expressio...