PMID- 35642038 OWN - NLM STAT- MEDLINE DCOM- 20220602 LR - 20230916 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 20 IP - 1 DP - 2022 May 31 TI - mTOR pathway gene mutations predict response to immune checkpoint inhibitors in multiple cancers. PG - 247 LID - 10.1186/s12967-022-03436-1 [doi] LID - 247 AB - 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 expression. Immunologically, pathways involved in anti-tumor immune response were enriched in presence of this mutational signature in mTOR pathway, leading to increased infiltration of immune effector cells (e.g., CD8 + T cells, NK cells, and M1 macrophages), but decreased infiltration of immune inhibitory M2 macrophages. CONCLUSIONS: These results suggested that mTOR pathway gene mutations were predictive of better survival upon ICI treatment in multiple cancers, likely by its association with enhanced anti-tumor immunity. Larger studies are warranted to validate our findings. CI - (c) 2022. The Author(s). FAU - Cheng, Lei AU - Cheng L AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Wang, Yanan AU - Wang Y AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Qiu, Lixin AU - Qiu L AD - Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. FAU - Chang, Yuanyuan AU - Chang Y AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Lu, Haijiao AU - Lu H AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Liu, Chenchen AU - Liu C AD - Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. FAU - Zhang, Bo AU - Zhang B AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Zhou, Yan AU - Zhou Y AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Bai, Hao AU - Bai H AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. FAU - Xiong, Liwen AU - Xiong L AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. Xiong_li_wen@126.com. FAU - Zhong, Hua AU - Zhong H AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. eddiedong8@hotmail.com. FAU - Nie, Wei AU - Nie W AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. niewei-1001@163.com. FAU - Han, Baohui AU - Han B AUID- ORCID: 0000-0002-3950-3030 AD - Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, 20030, China. 18930858216@163.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220531 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (Biomarkers, Tumor) RN - 0 (Immune Checkpoint Inhibitors) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Biomarkers, Tumor/genetics/metabolism MH - Humans MH - *Immune Checkpoint Inhibitors/pharmacology/therapeutic use MH - Mutation/genetics MH - *Neoplasms/drug therapy/genetics MH - TOR Serine-Threonine Kinases/genetics PMC - PMC9153162 OTO - NOTNLM OT - Cancer OT - ICI OT - Prognosis OT - TMB OT - mTOR pathway COIS- The authors declare no potential conflicts of interest. EDAT- 2022/06/02 06:00 MHDA- 2022/06/03 06:00 PMCR- 2022/05/31 CRDT- 2022/06/01 00:21 PHST- 2022/02/03 00:00 [received] PHST- 2022/05/12 00:00 [accepted] PHST- 2022/06/01 00:21 [entrez] PHST- 2022/06/02 06:00 [pubmed] PHST- 2022/06/03 06:00 [medline] PHST- 2022/05/31 00:00 [pmc-release] AID - 10.1186/s12967-022-03436-1 [pii] AID - 3436 [pii] AID - 10.1186/s12967-022-03436-1 [doi] PST - epublish SO - J Transl Med. 2022 May 31;20(1):247. doi: 10.1186/s12967-022-03436-1.