The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression

Abstract

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4 T cells and CD8 T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. .

The Gut Microbiome in Pancreatic Disease

“…However, gut flora can migrate into the pancreas and may influence the pancreatic microenvironment even in subjects with an otherwise normal pancreas. 15 Gut microbiota alterations are found in pancreatic disease and may play a role in the pathogenesis of several pancreatic diseases including acute pancreatitis, chronic pancreatitis and pancreatic cancer. 14 However, there is still only limited evidence supporting a causal relationship between gut dysbiosis and pancreatic diseases.…”

“…58, 59 Consistent with their role in modulating the immune response, gut bacterial profiles are recognized as influencing the immune response directed towards tumors. 15, 60 Several studies have shown that gut microbiome profiles influence the immune therapy response to checkpoint inhibitor therapy. 61–63 …”

“…67 Other oral microbial differences found between patient groups with pancreatic cancer, chronic pancreatitis and healthy controls were described by Farrell et al 68 Since these were case/control studies, it is not yet clear if these microbial changes contribute to disease pathogenesis or are merely a consequence of the disease. Recent studies have also identified bacteria within the tumor microenvironment of human pancreatic cancers 15 and within other tumors. 69 The bacteria identified in human pancreatic cancers are representative of the major genus of gut bacteria such as Proteobacteria .…”

“…69 The bacteria identified in human pancreatic cancers are representative of the major genus of gut bacteria such as Proteobacteria . 6915 Recent studies in genetically engineered mouse models of pancreatic neoplasia have shed additional light on the role of gut bacteria in pancreatic tumorigenesis. Using the Ptf1a Cre ; LSL-Kras G12D (KC) and Ptf1a Cre , LSL-Kras G12D , Trp53 R172H (KPC) mouse models of pancreatic neoplasia, Pushalkar et al found oral antibiotics protected against neoplastic progression.…”

Adoptive CD8+ T cell therapy against cancer:Challenges and opportunities

“…Intratumor host accessory cells include cancer-associated fibroblast [35], endothelial cells [36], pericytes [37], immunosuppressive immune cells (Treg, tumor- Table 1 Selected TCR-T trails against common tumor antigen for tumors. associated macrophages, tolerogenic dendritic cells, Breg, myeloid-derived suppressor cells, mast cells) [38,39]. These accessory cells create immunosuppressive TME via pathways including 1) creating and reinforcing immune checkpoints [40]; 2) secreting immune suppressive cytokines e.g.…”