Abstract A099: Standard chemotherapy in patients with pancreatic ductal adenocarcinoma modulates B cell education within and outside tertiary lymphoid structures

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the world. The standard treatment for PDAC consists of surgical resection when possible and perioperative combination chemotherapy regimens, including Gemcitabine-Abraxane (Gem/Abraxane) and FOLFIRINOX. Recent studies have shown increased survival probability associated with higher B cell infiltration. B cells are a heterogenous population and can promote antitumor immunity by mediating humoral immunity in response to antigen stimulation. Naïve B cells will differentiate into memory B cells (MBCs) or plasma cells through a germinal center (GC)-associated response and/or the extrafollicular (EF) response. The GC-associated response intratumorally occurs within tertiary lymphoid structures (TLS). TLS are ectopic lymphoid organs that arise in sites of chronic inflammation and vary in formation with more functional and active TLS classified by containing GC with follicular dendritic cells (fDCs). Therapeutics, such as chemotherapy, can alter prevalence and activity of TLS by increasing tumor antigen availability and activating an inflammatory signaling cascade leading to an influx of immune cells. We hypothesized that standard of care chemotherapy (Gem/Abraxane) would increase the production of antibody secreting cells (ASCs) through amplification of the GC-associated and EF response. We aimed to understand these responses in PDAC patients via multispectral imaging of patient tumors and ex vivo phenotyping and in vitro modulation of B cells via patient derived organoids (PDOs). We studied the GC-associated response by analyzing TLS states in primary resected tissue from PDAC patients. The patients were either treatment naïve or treated with Gem/Abraxane. We found an increase in GC-associated responses and increased TLS activity in the Gem/Abraxane-treated patients. Further, we analyzed the abundance of MBCs and ASCs in paired patient peripheral blood mononuclear cells both pre and post Gem/Abraxane-treatment using spectral flow cytometry. The post treatment samples from the patients had increased production of ASCs and MBCs associated with the EF response. We tested the effect of the PDAC tumor microenvironment on altering naïve B cell differentiation toward MBCs via the GC-associated and EF pathway by performing an in vitro differentiation assay using conditioned media from PDAC treatment naïve or Gem/Abraxane PDOs. The naïve B cells cultured with the Gem/Abraxane conditioned media compared to the treatment naïve had increased production of ASCs at an earlier time point indicative of an EF response. Together, our findings highlight the importance of understanding the effects of standard treatment on altering the humoral response which modulates MBC and ASC production and can lead to an improved antitumor response in patients with PDAC. These findings provide rationale for designing B cell targeted immunotherapies in PDAC patients in complement standard treatment strategies. Citation Format: Charu Arora, Renee Anderko, Adam Tcharni, Sheryl Kunning, Tullia Bruno. Standard chemotherapy in patients with pancreatic ductal adenocarcinoma modulates B cell education within and outside tertiary lymphoid structures [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A099.