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

Mengyao Wu¹Ge Li²Yecheng Li³Kai Chen¹Mengdan Xu¹Dapeng Li¹Caihua Xu¹Meng Shen^1*Wei Li^1*Jinming Cao^1*

• ¹First Affiliated Hospital of Soochow University, Suzhou, China
• ²Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
• ³Second Affiliated Hospital of Soochow University, Suzhou, China

Pancreatic ductal adenocarcinoma (PDAC) remains resistant to immunotherapy. This study evaluated the efficacy of combining immunotherapy with chemotherapy in advanced PDAC, alongside profiling the immune landscape and transcriptomic features. Data from 52 patients treated with this combination were reviewed, focusing on objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune profiling was performed using flow cytometry, multiplex immunofluorescence (mIF), and whole transcriptome shotgun sequencing (WTSS) on untreated tumor tissues and peripheral blood samples. The results showed 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 receiving immunotherapy combined with gemcitabine exhibited the longest PFS. The first-line treatment group demonstrated significantly higher DCR (79.3% vs. 52.2%, P = 0.038) and longer median PFS (6.6 vs. 3.5 months, P = 0.032) compared to the second-line group. Efficacy varied with different drug combinations. Flow cytometry revealed a higher frequency of CD45⁻ CD64⁺ cells in the peripheral blood of patients with progressive disease (PD) compared to those with partial response (PR). MIF analysis showed increased intratumoral infiltration of CD8⁺ T cells and CD137⁺ CD8⁺ T cells among PR patients. WTSS identified key genes associated with immune regulation, signal transduction, and digestive function. Hemopexin (HPX) and regulatory factor X-associated protein (RFXAP) were upregulated in PR patients and correlated positively with survival, whereas Interleukin-6 (IL-6) expression was associated with poor prognosis. These findings suggest that immunochemotherapy holds promise for advanced PDAC. Our study delineates the immune landscape of PDAC and offers valuable insights for identifying potential therapeutic targets, which may inform the development of novel combination immunotherapy strategies.