Abstract 1342: Evaluating the role of antibody in pancreatic tumorigenesis

Abstract

Abstract Introduction: Infiltrating pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of 10%. The PDAC tumor microenvironment (TME) is characterized by a fibroinflammatory response mediated by a complex mix of cancer-associated fibroblast (CAF) subsets resulting significant deposition of extracellular matrix (ECM), poor vascularization, T cell exclusion, and recruitment of immune-suppressive myeloid cells. Collectively, these factors contribute to a resistance to aggressive chemotherapeutics and failure of checkpoint inhibitors. Preclinical studies as well as clinical efforts designed to deplete the dense tumor stroma or ECM have been successful, but unexpectedly accelerated tumor progression underscoring critical gaps in our understanding of the dynamics between tumor, stromal elements, and infiltrating immune cell subsets. Rationale: In some cancer subtypes, B cells have been shown to suppress cancer progression through secretion of antibodies targeted to aberrantly expressed self-, stress-associated-, or tumor-specific antigens on neoplastic cells. A considerable body of literature also indicates that B cells may play a role in promotion of pancreatic tumor progression, however, the role of antibodies in PDAC progression is unclear. The major objective of our studies is to understand the significance of anti-tumor antibody responses in pancreatic tumorigenesis. Methods: To address this question, we crossed the spontaneous mouse model of pancreatic cancer where Pdx1 drives Cre-mediated activation of a mutant KrasG12D allele on a heterozygous Tp53+/FL mutant background (KPC-WT mice) with animals that retain B cells that lack the ability to secrete antibody of any immunoglobulin (Ig) isotype (KPC-μS-AID mice). Results: Kaplan-Meier survival studies demonstrate that loss of all circulating antibody accelerates progression to lethal PDAC in KPC-μS-AID versus KPC-WT mice (median survival of 3- versus 5-months, respectively), with increased incidence of lung and liver metastases. Further, loss of circulating antibodies increased the density of intratumoral neutrophils, reduced numbers of podoplanin+ CAFs and reduced ECM density. IgG subclass antibodies were localized at higher densities within stroma/ECM in pancreata from both mice and surgically resected tumor specimens from human PDAC patients. Loss of AID-dependent class switched antibodies similarly accelerated lethal PDAC in KPC-AID versus KPC-WT mice. Conclusions: These findings implicate class-switched antibodies in delaying pancreatic tumor progression through potential regulation of intratumoral neutrophil density and ECM production within the PDAC TME. Citation Format: Jeremy Foote. Evaluating the role of antibody in pancreatic tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1342.