Abstract IA13: Regulation of pancreatic oncogenesis by pathogens
Authors: Miller George 
Published: December 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a devastating disease in which the mortality rate approaches the incidence rate. PDA is characterized by immune suppression. Specifically, the PDA tumor microenvironment in the majority of patients and in animal models of disease is associated with a modest T-cell infiltrate, dominated by Th2- and Treg-polarized CD4+ T cells and a paucity of cytotoxic CD8+ T cells. We and others have shown that the tolerogenic T-cell environment in PDA is programmed by suppressive myeloid cell elements. M2-polarized tumor-associated macrophages (TAMs) promote the differentiation of immune-suppressive Th2 cells and Tregs. Further, myeloid-derived suppressor cells (MDSC) veto cytotoxic CD8+ T-cell responses. As a consequence of the resultant immune anergy, immunotherapy has not been efficacious in this disease. Underlying all this, we found that the suppressive myeloid cell programming in PDA is dictated by the distinctive PDA-associated microbiome, which promotes accumulation of MDSC and M2-polarized TAMs via the release of bacterial-derived motifs that ligate diverse pattern recognition receptors in myeloid cells, leading to tumor-promoting myeloid cell differentiation and inflammation, which leads to adaptive immune collapse. In parallel to our interest in the role of the bacterial microbiome in oncogenesis, we developed an interest in the role of the fungal mycobiome. As we became interested in characterizing immune-modulatory sterile ligands for C-type lectin receptors (CLRs), which are cousins to TLRs, we identified Galectin-9 as a binding partner for Dectin-1 and SAP130 as a binding partner for Mincle in the tumor microenvironment. While our identification of sterile ligands for CLRs in cancer is interesting, the “natural” ligands for CLRs are fungal wall carbohydrate polymers. As such, we postulated that fungi may modulate the intratumoral inflammation and influence oncogenesis. We found that human pancreatic tumors and mouse models of this cancer displayed an increase in fungi of about 3,000-fold compared to normal pancreatic tissue. The composition of the mycobiome of PDA tumors was distinct from that of the gut or normal pancreas. Specifically, the fungal community that infiltrated PDA tumors was markedly enriched for Malassezia spp. in both mice and humans. Ablation of the mycobiome was protective against tumor growth, whereas repopulation with a Malassezia species—but not other species—accelerated oncogenesis. We also discovered that ligation of the CLR mannose-binding lectin (MBL), which binds to glycans of the fungal wall to activate the complement cascade, was required for oncogenic progression, whereas deletion of MBL or C3 in the extratumoral compartment—and knockdown of C3aR in tumor cells—were both protective against tumor growth. Collectively, our work revealed that pathogenic fungi promote PDA by driving the complement cascade through the activation of MBL.
Citation Format: George Miller. Regulation of pancreatic oncogenesis by pathogens [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 IA13.