Prognostic value and immunological significance of t-cell proliferation regulators in pancreatic cancer: a novel predictive model

BackgroundPancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, limiting the efficacy of immunotherapy. T-cell regulation plays a pivotal role in anti-tumor immunity. However, the prognostic value and therapeutic implications of T-cell regulation-related genes (TRGs) in PC remain largely unexplored. This study aims to construct a TRG-based risk model and validate key therapeutic targets.MethodsTranscriptomic profiles and clinical data were retrieved from TCGA and GEO databases. Non-negative Matrix Factorization (NMF) clustering was performed to identify molecular subtypes. A prognostic risk signature was constructed using LASSO regression analysis. The immune landscape was evaluated via ssGSEA, CIBERSORT and TIDE algorithms. A nomogram was established to predict overall survival, and drug sensitivity was assessed based on IC50 estimation. Crucially, the expression of the key signature gene IL1RN was validated in clinical tissues using qRT-PCR, Western Blot, and immunohistochemistry (IHC). Its function in T-cell mediated cytotoxicity was further verified using co-culture assays.ResultsTwo distinct molecular subtypes were identified, with Cluster 1 exhibiting an immune-hot phenotype and superior survival. A robust risk model was constructed and validated, serving as an independent prognostic factor. High-risk patients were characterized by an immune-excluded phenotype but showed higher sensitivity to chemotherapeutic agents like Gemcitabine. Experimental validation confirmed that IL1RN was significantly upregulated in PC tissues. Functionally, knockdown of IL1RN significantly enhanced the cytotoxicity of T cells against pancreatic cancer cells in vitro.ConclusionWe constructed a novel TRG-based prognostic signature that can serve as an auxiliary tool for clinical prognostic evaluation in pancreatic cancer. Furthermore, we validated IL1RN as a critical mechanism of immune resistance. IL1RN is expected to become a novel target for pancreatic cancer immunotherapy, providing experimental evidence for the stratified treatment of PC.