Multi-omics analyses inform mechanisms of immunotherapy response in pancreatic cancer.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) continues to exhibit resistance to immunotherapy. In this study, we evaluated the efficacy of combining immunotherapy with chemotherapy for the treatment of advanced pancreatic cancer. Additionally, we employed a multimodal analytical approach to elucidate the immune landscape and conduct transcriptomic profiling in PDAC. Methods: A retrospective analysis was conducted on the clinical data of 52 patients diagnosed with advanced PDAC who underwent a combined treatment regimen of immunotherapy and chemotherapy. The study evaluated the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). To characterize the immune landscape in treatment-naive pancreatic ductal adenocarcinoma (PDAC) tumors and in the systemic circulation, flow cytometry, multiplex immunohistochemistry (mIHC), and whole transcriptome sequencing were employed. Results: The study reported an ORR of 32.7%, a DCR of 67.3%, and a 6-month PFS rate of 38.5%, with a median PFS of 5.5 months. Patients treated with a combination of immunotherapy and gemcitabine achieved the longest PFS. The first-line treatment cohort exhibited a significantly higher DCR (79.3% vs. 52.2%, P = 0.038) and a longer median PFS (6.6 vs. 3.5 months, P = 0.032) compared to the second-line treatment cohort. The efficacy of treatment varied depending on the drug combinations used. Flow cytometry analysis revealed a greater frequency of CD45- CD64+ cells in the peripheral blood of patients with progressive disease (PD) compared to those with a partial response (PR). Multiplex immunofluorescence (MIF) analysis indicated an increased intratumoral infiltration of CD8+ T cells and CD137+ CD8+ T cells in patients with PR. Whole transcriptome sequencing (WTSS) identified key genes involved in immune regulation, signal transduction, and digestive function. Hemopexin (HPX) and regulatory factor X-associated protein (RFXAP) were upregulated in PR patients and showed a positive correlation with survival, whereas Interleukin-6 (IL-6) expression was linked to poor prognosis. Conclusions: These findings indicate that immunochemotherapy shows potential for the treatment of advanced PDAC. Our study elucidates the immune landscape associated with PDAC and provides critical insights for the identification of prospective therapeutic targets, which could guide the development of innovative combination immunotherapy strategies.