Prognostic and predictive value of YTHDF1 and YTHDF2 and their correlation with tumor-infiltrating immune cells in non-small cell carcinoma

BACKGROUND: YTH domain-containing family protein 1 (YTHDF1) or YTHDF2 play crucial roles in cancer immunotherapy. We examine the expression of YTHDF1, YTHDF2, CD8, CD4, and FOXP3 to identify their prognostic or predictive role for PD-1/PD-L1 inhibitor in non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical expression of YTHDF1, YTHDF2, CD8, CD4, and FOXP3 was investigated in 266 patients not receiving PD-1/PD-L1 inhibitors and in 59 patients receiving PD-1/PD-L1 inhibitors. Immunohistochemical results were verified using mRNA dataset obtained from The Cancer Genome Atlas (TCGA) database. RESULTS: Immunohistochemical expression of YTHDF1 or YTHDF2 was negatively associated with CD8- and CD4-positive T cells; however, the same expression was positively associated with FOXP3-positive T cells. YTHDF1 or YTHDF2 mRNA expression was also negatively associated with CD8- and CD4-positive T cells. Gene set enrichment analysis revealed that low YTHDF1 was related to immune hot tumor gene sets. Expression of YTHDF1 or YTHDF2 was negatively associated with expression of most immune checkpoints. YTHDF1 and YTHDF2 were predictive markers of response to PD-1/PD-L1 inhibitors. YTHDF1 or YTHDF2 expression was associated with better prognosis. YTHDF1 has an immune hot profile in both cell types, whereas YTHDF2 is only seen in adenocarcinoma. CONCLUSION: Low YTHDF1 or YTHDF2 reflects an immune hot tumor signature and may serve as a predictor or prognostic marker.