Th2-MPP Cells Shape an Immunosuppressive Microenvironment in ccRCC: Development of a Prognostic Signature and Functional Validation of ITPKA

Abstract Background: Clear cell renal cell carcinoma (ccRCC), frequently characterized by the infiltration of type II T helper (Th2) cells, necessitates the development of reliable prognostic models and the discovery of new biomarkers to advance personalized treatment approaches. Th2-multipotent progenitor (Th2-MPP) cells, a recently identified subset of T-cells, have been linked to chronic type II inflammation. Methods: Multiple machine learning algorithms and their combinations were utilized to establish a robust Th2-MPP-related score (T2Ms) for predicting prognosis and response to PD-1 blockade therapy in ccRCC patients. Functional enrichment analysis and the TimiGP algorithm were used to investigate the potential mechanisms of T2Ms in ccRCC, and integrative analysis was employed to identify key T2Ms-associated genes. Results: Pan-cancer analysis revealed elevated expression of Th2-MPP signature genes in malignant ccRCC. A stable T2Ms scoring system was constructed and validated using three independent cohorts. T2Ms accurately predicted patient prognosis and response to PD-1 blockade therapy. Core biological processes associated with Th2-MPP were linked to chronic type II inflammatory responses. ITPKA was identified as a key T2Ms-related gene and an independent predictor of poor prognosis, with high expression correlating with inferior response to PD-1 blockade. The consistent upregulation of ITPKA at the protein level, corroborating our mRNA findings, prompted us to further investigate its functional role in ccRCC cell lines. Conclusion: This study suggests that Th2-MPP cells may be enriched in ccRCC and provides a Th2-MPP-based signature for predicting prognosis and therapeutic response to PD-1 inhibition. ITPKA was identified as a critical factor in the T2Ms model and as a potential biomarker for tumor-associated Th2-MPP cells.