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Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy
Jun-Yu Long1, Rui-Zhe Li2, Dong-Xu Wang2
1Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Beijing, PR China.
Background:
The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy.
Method:
We analysed the role of RET mutations in predicting the prognosis of patients 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 tumour inflamed anti-tumour immune response and tumour antigenicity.
Results:
Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy.
Conclusions:
RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.
Insights
RET mutations are linked to better outcomes in immune checkpoint inhibitor (ICI) therapy across multiple cancers. These RET mutations may serve as a biomarker for predicting a stronger response to ICI treatments.
Area of Science:
- Oncology
- Immunotherapy
- Cancer Genetics
Background:
- The RET gene is frequently mutated in various cancers, playing a role in tumorigenesis.
- The predictive value of RET mutations for immune checkpoint inhibitor (ICI) therapy efficacy is not well understood.
Purpose of the Study:
- To investigate the association between RET mutations and the effectiveness of ICI therapy.
- To determine if RET mutations can predict patient prognosis during ICI treatment.
Main Methods:
- Retrospective analysis of patient cohorts treated with ICIs to assess RET mutation status and clinical outcomes.
- Validation of findings in an independent patient cohort.
- Multi-omics data analysis (TCGA pan-cancer cohort) to explore the relationship between RET mutations and anti-tumor immune responses, tumor antigenicity, and immune cell infiltration.
Main Results:
- RET mutations were associated with improved response rates, progression-free survival (PFS), and overall survival (OS) in patients receiving ICI therapy across five cancer types.
- Multivariate analysis confirmed RET mutation as an independent predictor of prognosis in patients treated with ICIs.
- Subgroup analysis indicated that significant differences in OS and PFS between RET-mutant and RET-wildtype tumors were observed primarily in the monotherapy group.
- Multi-omics data suggested that RET-mutant tumors exhibit enhanced immunogenicity, higher immune checkpoint and chemokine expression, and increased immune cell infiltration, potentially contributing to a better response to immunotherapy.
Conclusions:
- RET mutation may serve as a predictive biomarker for enhanced response to ICI therapy.
- Further research into the molecular mechanisms and prospective clinical studies are warranted to confirm these findings.
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