DPP4 Promotes Papillary Thyroid Cancer Progression by Regulating the Infiltration and Exhaustion of CD8+ T cells

Abstract Background: Papillary thyroid cancer (PTC) is one of the most prevalent endocrine malignancy with a rapidly increasing incidence worldwide, a special immune microenvironment of which is not well characterized. Thus, the aim of this study was to identify the key biomarkers that regulate immune cells for the development and recurrence of PTC. Methods: The expression of immune-associated differentially expressed genes (DEGs) in human PTC was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT and TIMER tool was used to analyze the distribution of tumor1infiltrating immune cells in PTC. Furthermore, DEG expression and function for the infiltration of CD8+ T cells were explored using human PTC specimens. Results: In this study, we identified DPP4 as a key gene in PTC by differential expression analysis among four GEO datasets and TCGA dataset and validated its overexpression profile by data from the TCGA, HPA databases, WB and PCR analysis. DPP4 upregulation significantly correlated with advanced grades, stages, and poor progression-free survival.Based on TIMER and CIBERSORT analysis, DPP4 expression tightly correlated with the infiltration of diverse immune cell types, especially CD8+ T cell subtypes. Compared with benign thyroid tumor, the proportion of CD3+CD8+ T cells in peripheral blood of PTC patients was significantly decreased, while the CD3+CD8+DPP4+ T cells of PTC patients was increased. The relative expression of PD-L1 and CTLA-4 in the CD8+DPP4+ T cells of PTC patients was higher than that in the CD8+DPP4- T cells. In addition, CD8+DPP4+ T cells of PTC patients showed the lower expression of IFN-γ and increased expression of IL-13 than that in benign thyroid tumor. The relative expression of IFN-γ, TNF-α, IL-4, IL-5, and IL-13 in CD8+DPP4+ T cells were both lower than that in CD8+DPP4- T cells among PTC and benign thyroid tumor patients. Conclusion: Our work suggests that the immune-associated DEG DPP4 is upregulated in PTC tissues and is tightly correlated with clinical stages and outcomes and regulates immune infiltration, but in particular involves in CD8+ T cell evasion and exhaustion. These findings may offer a new prospect for targeting CD8+ T cell exhaustion therapies for the treatment of PTC.