MTHFR act as a potential cancer biomarker in immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration

Abstract

Abstract Purpose To evaluate the role and landscape of 5-10-Methylenetetrahydrofolate reductase (MTHFR) to immune infiltration, tumor microenvironment, heterogeneity, immune checkpoints blockades, prognostic significance across cancer types. Methods Data sets of genomic, transcriptomic and clinic features of MTHFR across >60,000 patients and up to 44 cancer types were comprehensively analyzed using R software. Results Expression of MTHFR gene is significantly lower in 17 tumors and correlated with OS, DSS, PFI in specific tumors. Gene alterations of MTHFR are observed significant differences across tumor types. Expression of MTHFR is negatively correlated with the mDNAsi, mRNAsi, DMPsi, ENHsi, EREG-mDNAsi and EREG-mRNAsi in the most cancers. MTHFR showed significantly correlated with 67 types of immune cell infiltration scores in 44 cancer types by XCELL algorithm. GO and KEGG enrichment analysis are conducted to show the core tumor mechanism and biological process. Correlations between MTHFR and biomarkers of heterogeneity (MSI, TMB, MATH, HRD, LOH, Neoantigen, ploidy and purity) are also significant in specific tumors. MTHFR is significantly positively correlated with biomarkers of immune related genes (CD19, CD274, CD80, CD86) and mismatched repair genes (MLH1, PMS2, MSH2, MSH6, EPCAM, MLH3, PMS1, EXO1) in most cancer types. ROC analyses show MTHFR could act as a biomarker in anti-PD1 and anti-CTLA4 group of ontreatment, in anti-PD1 (pembrolizumab) group in pretreatment. Two immunohistochemistry antibodies HPA076180 and HPA077255 are verified in 20 types of tumor and could be used to detect the expression of MTHFR efficientlyin clinic. Conclusions MTHFR could predict the response of immune checkpoints blockades, heterogeneity, tumor microenvironment and immune infiltration.