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. .

Summary Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely-activated γδT cell population which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1-polarization of αβT cells. Whereas αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor-protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor-protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intra-tumoral immune tolerance are uncertain. Dectin-1 is an innate immune receptor critical in anti-fungal immunity, but its role in sterile inflammation and oncogenesis is not well-defined. Further, non-pathogen-derived ligands for Dectin-1 have not been characterized. We found that Dectin-1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin-1 ligation accelerated PDA, whereas Dectin-1 deletion or blockade of its downstream signaling was protective. We found that Dectin-1 ligates the lectin Galectin-9 in the PDA tumor microenvironment resulting in tolerogenic macrophage programming and adaptive immune suppression. Upon interruption of the Dectin-1–Galectin-9 axis, CD4+ and CD8+ T cells – which are dispensable to PDA progression in hosts with an intact signaling axis – become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting Dectin-1 signaling is an attractive strategy for the immunotherapy of PDA.

Daley et al. show that NLRP3 signaling in macrophages drives their immune-suppressive phenotype in the pancreatic tumor microenvironment and potentiates tolerogenic T cell differentiation. Conversely, targeting NLRP3 protects against pancreatic oncogenesis and is associated with immunogenic reprograming within the tumor.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 − DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ + regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 + T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 − DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy.

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