Novel Insights into T-Cell Exhaustion and Cancer Biomarkers in PDAC Using ScRNA-Seq

One of the aggressive and lethal cancers, pancreatic ductal adenocarcinoma (PDAC) is characterised by poor prognosis and resistance to conventional treatments. Moreover, tumor immune microenvironment (TIME) plays a crucial role in the progression and therapeutic resistance of PDAC. It is associated with T-cells exhaustion, leading to the progressive loss of T-cell functions with impaired ability to kill tumor cells. Therefore, this study employed single cell RNA sequencing (scRNA-seq) analysis and identified upregulated genes of cancer cells in two groups (“cancer cells_vs_all-PDAC” and “cancer-PDAC_vs_all-normal”), while of T-cells, including CD8+ NKT-like cells, memory CD4+ T-cells, and naive CD4+ T-cells were identified between conditions (PDAC_vs_Normal) with their respective cell types. Subsequently, common and unique markers of cancer cells from both groups were identified, resulting in three sub-groups (common in both groups, unique to “cancer cells_vs_all-PDAC” and unique to “cancer-PDAC_vs_all-normal” group). Moreover, the top-10 enriched Reactome pathways of cancer cells (common and unique) and T-cells were identified; and the genes implicated in those pathways were selected to perform PPI analysis, eventually revealing the top-10 hub-genes of each group (common and unique) of cancer cells ( GAPDH, AKT1, EGFR, CS, RHOA, TPI1, SDHA, TFRC, FASN, HIF1A, H4C6, MYC, H3C12, DDX21, USP7, RFC4, APEX1, CDK9, H2BC9, NOP2, FN1, COL1A1, COL1A2, COL3A1, COL5A2, COL6A1, COL5A1, BGN, COL6A2, and FBN1 ) and T-cells ( ACTB, AKT1, CD4, CTNNB1, FN1, H3-3B, HIF1A, HSP90AA1, HSP90AB1, HSPA8, IFNG, ITGB1, JUN, MAPK3, MMP9, NFKB1, TP53, UBB, and UBC ). Furthermore, the gene expression validation of cancer cell and T-cells hub-genes was performed using GEPIA2 and TISCH2, while overall survival analysis of cancer cell hub-genes was performed using GEPIA2. Conclusively, this study unravelled a total of 16 novel markers ( CS, H4C6, H3C12, H2BC9, TP53, FN1, MMP9, ITGB1, HSP90AB1, AKT1, ACTB, MAPK3, UBC, UBB, CTNNB1, and H3-3B ) of cancer and T-cells, indicating that these might be implicated in the pathways leading to T-cell exhaustion, rendering growth, proliferation, and survival of cancer cells. This study provides the groundwork for future research into the immune landscape of PDAC, particularly T-cell exhaustion. However, further clinical studies are needed to validate these novel markers as potential therapeutic targets in PDAC patients.