Construction and validation of a RARRES3-based prognostic signature related to the specific immune microenvironment of pancreatic cancer.

BACKGROUND: Tumor immune microenvironment (TiME) is prognostically instructive in Pancreatic adenocarcinoma (PAAD). However, the potential value of TiME-related genes in the individualized immunotherapy of PAAD has not been clarified.

METHODS: Correlation between Immune-Related Genes (IRGs) and immune-related transcription factors (TFs) was performed to prove the immune correlation of selected genes. Immune-related molecular subtypes were identified by consensus clustering. The TiME-score, an immune microenvironment-related prognostic signature for PAAD, was constructed using minimum absolute contraction and selection operator regression (Lasso-Cox). The International Cancer Genome Consortium (ICGC) dataset validated the reliability of TiME-score as external validation. Single-cell samples from GSE197177 confirmed microenvironment differences of TiME-score hub genes between tumor and its paracancer tissues. Then, RARRES3, a hub gene in TiME-score, was further analyzed about its upstream TP53 mutation and the specific immune landscape of itself in transcriptome and Single-cell level. Eventually, TiME-score were validated in different therapeutic cohorts of PAAD mice models.

RESULTS: A 14-genes PAAD immune-related risk signature, TiME-score, was constructed based on IRGs. The differences of TiME-score hub genes in single-cell samples of PAAD cancer tissues and adjacent tissues were consistent with the transcriptome. Single-cell samples of cancer tissues showed more pronounced immune cell infiltration. The upstream mutation factor TP53 of RARRES3 was significantly enriched in immune-related biological processes. High RARRES3 expression was correlated with a worse prognosis and high macrophages M1 infiltration. Additionally, the immunohistochemistry of hub genes AGT, DEFB1, GH1, IL20RB, and TRAF3 in different treatment cohorts of mice PAAD models were consistent with the predicted results. The combination of immunotherapy, chemotherapy and targeted therapy has shown significantly better therapeutic effects than single drug therapy in PAAD.

CONCLUSION: TiME-score, as a prognostic signature related to PAAD-specific immune microenvironment constructed based on RARRES3, has predictive value for prognosis and the potential to guide individualized immunotherapy for PAAD patients.