RET mutation as a putative prognostic biomarker for immune checkpoint inhibitors therapy in various malignancies

Abstract

Abstract Background The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumor development, while its precise contribution to immune checkpoint inhibitors (ICIs) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICIs therapy.Method We analyzed the role of RET mutations in predicting the prognosis of patient receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumor inflamed anti-tumor immune response and tumor antigenicity.Results Our study revealed that RET mutation is associated with better clinical outcomes for ICIs therapy in 606 cases across five types of cancer, including elevated response rate, longer PFS and OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of ICIs-treated patients after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICI immunotherapy was further validated in the validation cohort (n = 1683). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS and PFS between RET- wildtype tumors and RET- mutant tumors. Multi-omics data analysis revealed potential anti-tumor immunity mechanisms of RET mutations, suggesting that RET-mutant tumors have enhanced immunogenicity, higher expression of immune checkpoints, chemokines, and immune cell infiltration than RET-wildtype tumors, potentially indicating a more favorable response to immunotherapy.Conclusions RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive molecular mechanism investigation and prospective studies are needed in the future.