Abstract C060: Adipose-tumor crosstalk alters tumor immune profile by promoting PDAC CXCL5 secretion

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death in the US, due to late detection and limited therapeutic options. While the main cause of PDAC remains unknown, obesity has been shown to be a major risk factor. However, the molecular mechanisms behind adipose-tumor crosstalk are still being elucidated. Therefore, understanding the crosstalk between adipose and PDAC is critical for improving therapeutic approaches. We hypothesize that factors secreted by the adipose tissue reprogram pancreatic cancer cells to drive tumor growth and anti-tumor immunity. We observed enhanced proliferation in cells treated with conditioned media made from adipose tissue collected from PDAC [MV1] patients. Subsequent analysis determined that PDAC cells also secrete high levels of CXCL5 in response to stimulation with adipose conditioned media. Pathway analysis of RNA-sequencing data from conditioned-media-treated human PDAC cell lines implicated IL-1β and TNF-α as being involved in the resulting transcript changes. Using recombinant IL-1β, we stimulated CXCL5 secretion from multiple PDAC cell lines. Additionally, we found an enhanced secretion of IL-1β from obese adipose tissue compared to that from lean adipose and, using an anti-IL-1β blocking antibody we were able to partially depress the CXCL5 secretion from cells stimulated with adipose conditioned media. Because CXCL5 is a known neutrophil activating and attracting protein, we used CRISPR to engineer CXCL5 deficient murine PDAC cells. To determine the effect of tumor-derived CXCL5 on PDAC growth and immune recruitment, we orthotopically injected non-targeting-control and CXCL5-KO K8484 cells into wild-type, syngeneic, obese mice. While CXCL5-KO tumors displayed a similar size, we observed a significant change in the tumor immune profile. Despite an increase in the pro-tumorigenic monocytic myeloid derived suppressor cells (MDSCs), we found that the CXCL5-KO tumors exhibited a significantly enhanced CD8+ T cell infiltration. However, a high percentage of these CD8+ T cells were PD-1 positive, implicating an exhausted phenotype. Subsequently, we treated wildtype and CXCL5 deficient PDAC bearing obese mice with an anti-PD-1 antibody to promote T-cell re-activation, which resulted in a significantly reduced growth of the CXCL5 deficient tumors. In conclusion, obesity and adipose derived factors directly induce tumor cells to support immune suppression and drive PDAC progression. Citation Format: R. McKinnon Walsh, Joseph Ambrose, Bailey A. Bye, Austin E. Eades, Jarrid L. Jack, Mariana T. Ruckert, Appolinaire A. Olou, Fanuel Messaggio, Prabhakar Chalise, Dong Pei, Michael N. VanSaun. Adipose-tumor crosstalk alters tumor immune profile by promoting PDAC CXCL5 secretion [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C060.