An integrative analysis revealing POLD2 as a tumor suppressive immune protein and prognostic biomarker in pan-cancer

Introduction: POLD2 is an indispensable subunit of DNA polymerase δ, which is responsible for the synthesis of the backward accompanying strand in eukaryotic organisms. Current studies have found an association between POLD2 and the development of a variety of cancers. However, its value in cancer immunotherapy has not been fully established. Methods: POLD2 expression was analyzed using RNA expression and clinical data from TCGA and GTEx databases. The prognostic impact of POLD2 on tumor patients was analyzed using clinical survival data from TCGA. Gene enrichment analysis was performed using the R package "cluster analyzer" to explore the role of POLD2. We used the TIMER2 database to analyze the relationship between immune cell infiltration and POLD2 expression in TCGA. We downloaded relevant data from TCGA and analyzed the relationship between POLD2 and immune checkpoints, immunosuppressive genes, immune activating genes, chemokines and chemokine receptors. Results: POLD2 was significantly overexpressed in most tumors compared to normal tissue. High POLD2 expression was significantly associated with advanced tumor stage, significantly shorter overall survival and progression-free survival. Also, we found that POLD2 expression correlated strongly with immunomodulatory genes, and significantly negatively with most immune checkpoints (PD-L1, CTLA4, TIM3, and CD28). Pathway enrichment analysis suggests that low expression of POLD2 promotes immune regulation-related pathways and high expression promotes metabolic and DNA repair-related pathways. Furthermore, tumor microenvironment analysis suggests that high POLD2 expression inhibits infiltration of CD8⁺ T cells and CD4⁺ memory T cells. Discussion: In conclusion, POLD2 may be a molecular biomarker for pan-cancer prognosis and immunotherapy. It may serve as a potential target for new insights in human tumor prognosis prediction and immunotherapy assessment.