Abstract A006: Outcomes from borderline resectable pancreatic ductal adenocarcinoma treated with immune checkpoint inhibition are associated with distinct features of lymphoid aggregates and plasma cell abundance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a 5 year survival rate of approximately 13% in the United States. Immune checkpoint inhibitors (ICIs) have limited efficacy in PDAC, likely due to its immunosuppressive tumor immune microenvironment (TIME) and barriers to immune cell infiltration; however, nearly all trials have evaluated ICIs in patients with metastatic PDAC. In a single-arm, phase I/II trial, we investigated the immune-related effects of standard of care FOLFIRINOX (FFX) with PD-1 inhibition (PD-1i, nivolumab) in patients with borderline-resectable PDAC; a stage at which the disease is restricted to the pancreas and can be typically converted to resectable status, yielding abundant tumor material for analyses. We performed immunohistochemistry on 20 resected tumors using markers for lymphoid aggregates (LAs): CD20, CD3, CD4, CD8, CD23, and MUM1 to investigate organized immune responses after chemotherapy with ICI. We assessed >400 lymphoid aggregates (LAs) by area, cell number, cell density, and presence of follicular dendritic cells (CD23+) and identified 3 distinct phenotypes: 1) large, highly cellular, CD23+ mature tertiary lymphoid structures (TLS); 2) LAs with high B cell density; and 3) tumor beds with dense LAs (number per mm2). None of the three features correlated with the presence of remnant tumor (i.e., pathologic response), only B cell density significantly correlated with nodal involvement (P<0.0001), and only LA density correlated with intra-tumoral plasma cell density (P=0.0001). We performed Xenium 5K Prime image-based spatial transcriptomics on 6 patient tumors in the study to define the unique functional phenotypes of cells within and around LAs. To characterize tumor infiltrating leukocytes throughout the TIME, we performed RNA sequencing and CIBERSORT deconvolution on 6 pre-treatment biopsies from the trial, 21 resected tumors after FFX+PD-1i treatment (5 matched to pre-treatment biopsies), and 9 resected tumors from patients treated with FFX alone. Although FFX+PD-1i treatment increased most leukocyte types, only plasma cell scores were significantly higher in FFX+PD-1i treated tumors compared to those treated with FFX alone (P=0.002). Additionally, plasma cells were significantly more abundant in less aggressive, classical subtype tumors compared to basal-like subtype tumors (P=0.003). Although plasma cell abundance alone was not prognostic for overall survival, patients with high plasma cell scores and low tumor burden (normal CA19-9 at surgery) survived significantly longer than all other patients (HR:0.22, 95% CI: 0.049-0.97, P=0.045). Our findings reveal distinct features of LAs in the setting of FFX+PD-1i for borderline-resectable PDAC, and that subsets of patients with high CD20+ density in LAs or abundant intra-tumoral plasma cells may benefit in this setting. Citation Format: Serena Zheng, Michael Srienc, David Dawson, Alykhan Premji, Zev Wainberg, Jason Link, Timothy Donahue. Outcomes from borderline resectable pancreatic ductal adenocarcinoma treated with immune checkpoint inhibition are associated with distinct features of lymphoid aggregates and plasma cell abundance [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A006.