Background and aimOnly 10% of pancreatic ductal adenocarcinoma (PDAC) patients survive longer than five years. Factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients.MethodsThe immune-related gene expression profiles of resected PDAC tumors of patients who survived and remained recurrence-free of disease for ≥36 months (long-term survivors, n=10) were compared to patients who had survived ≤6 months (short-term survivors, n=10) due to tumor recurrence. Validation was performed by the spatial protein expression profile of immune cells using the GeoMx™ Digital Spatial Profiler. An independent cohort of samples consisting of 12 long-term survivors and 10 short-term survivors, was used for additional validation. The independent validation was performed by combining qualitative immunohistochemistry and quantitative protein expression profiling.ResultsB cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling (p=0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling in the discovery and the validation cohorts (p=0.002 and p=0.01, respectively). The higher number of infiltrated B cells was found mainly in the stromal compartments of PDAC samples and was exclusively found within tumor cells in long-term survivors.ConclusionThis is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found a higher number and a specific location of B cells in TIME of long-term survivors which emphasizes the importance of B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy associated with a poor prognosis. Only 10% of the patients survive longer than five years. So far, factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients. Methods: The immune-related gene expression profiles of surgically resected PDAC tumors of patients who survived and remained recurrence-free of disease for > 3 years (long-term survivors, n=10) were compared to PDAC tumors of patients who had survived ≤ 6 months (short-term survivors, n=10) due to tumor recurrence. Samples were profiled using the nCounter® PanCancer Immune Profiling Panel of NanoString Technology. Validation was performed by spatial analysis of immune cells using the GeoMx™ Digital Spatial Profiler. Results: Tumor-infiltrating B cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling (p=0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling (p=0.049). This increase was accompanied by more T cells and antigen-presenting cell infiltration. Moreover, the activated immune cells were found to infiltrate in between tumor cells as well as in stromal areas in long-term survivors. In contrast, the TIME of short-term survivors was characterized by a high density of immunosuppressive cells like CD25 and regulatory T cells infiltrating in a highly fibrotic vicinity. Conclusion: This is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found higher infiltration of B cells in TIME of long-term survivors which highlights the importance of targeting B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients. Citation Format: Hosein M. Aziz, Lawlaw Saida, Willem de Koning, Andrew Stubbs, Yunlei Li, Casper H. J. van Eijck, Dana A. M. Mustafa. The tumor immune microenvironment is decisive in the survival of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-118.