Abstract PR05: Elucidating role of bacteria during pancreatic ductal adenocarcinoma (PDAC)

Abstract

Abstract Long-term survival in pancreatic cancer (PC) is rare as only a minority of all resected patients survive for >5 years. Interestingly, somatic mutations do not predict long-term survivorship, highlighting the potential role of extrinsic factors. Recent studies have reported the role of the gut and tumor microbiome in pancreatic tumorigenesis and PC treatment responses. Since intratumoral bacteria have been detected in human PC tumors, possibly arising from relocation of intestinal bacteria, it is possible that intratumoral T cells get primed with microbial antigens within the tumor microenvironment. To reconstruct bacterial phylogenies, we performed prokaryotic 16S ribosomal RNA sequencing and immunoprofiling of PC tumors from “Long-Term Survivors-LTS” (>5y post-resection) and “Short-Term Survivors-STS” (<5y post-resection). Strikingly, we found that LTS from both discovery and validation cohorts had higher microbial diversity and LTS from both cohorts were enriched for a tumor microbial signature: Pseudoxanthomonas, Streptomyces, Saccharopolyspora, and Bacillus clausii. Moreover, the most overrepresented species in LTS tumors strongly correlated with enhanced immunoactivation of the tumor microenvironment, suggestive of bacterial-mediated immune cell recruitment and activation. Based on these findings, we hypothesized that gut bacteria affect PC by triggering immune responses either locally by migrating to the tumor or systemically through responses originating in the gut. To test this, we performed in vitro studies and found that single bacterial species identified from LTS tumor microbial signature can induce activation of cytotoxic T lymphocytes (CD8+ CD69+ IFNg+) only when in direct contact with antigen-presenting cells, suggesting that bacterial antigens need to be processed and presented to intratumoral T cells to induce their activation. Furthermore, through preliminary in vivo studies, we have found that orally administered single bacterial species can be delivered to the pancreas via the gut. Further work needs to determine whether single/specific LTS bacteria play a causative role in regulating tumor immunity in vivo. If the beneficial modulatory role of specific bacteria is established, then bacteriotherapy as single therapy or in combination with fecal microbial transplants could be used as innovative strategies for treatment of pancreatic cancer. This abstract is also being presented as Poster B27. Citation Format: Vidhi Chandra, Olivereen Le Roux, Erick Riquelme, Yu Zhang, Anirban Maitra, James. R White, Florencia McAllister. Elucidating role of bacteria during pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR05.