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 immunesuppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. SIGNIFICANCE: 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.
|Number of pages||14|
|State||Published - Apr 2018|
Bibliographical noteFunding Information:
This work was supported by NIH CA206105 (D. Saxena and G. Miller), CA168611 (G. Miller), CA155649 (G. Miller), DE025992 (D. Saxena), CA180277 (X. Li), CA175794 (A. Saxena), P40 OD010995 (R.B. Sartor), P30 DK034987 (R.B. Sartor), the Department of Defense Peer Reviewed Medical Research Program (G. Miller), the Lustgarten Foundation (D. Saxena and G. Miller), AACR-PanCan (G. Miller), the Panpaphian Association of America (C.P. Zambirinis), the National Pancreas Foundation (C.P. Zambirinis), Crohn’s and Colitis Foundation of America (R.B. Sartor), NYU Provost Office Mega Grant Seed Fund Initiative (D. Saxena and X. Li), and the Irene and Bernard Schwartz Fellowship in GI Oncology (D. Daley). We thank the New York University Langone Medical Center (NYULMC) Histopathology Core Facility, the NYULMC Flow Cytometry Core Facility, the NYULMC Microscopy Core Facility, and the NYULMC BioRepository Center, each supported in part by the Cancer Center Support Grant P30CA016087 and by grant UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS). KC mice were a gift of D. Bar-Sagi and KPC mice were a gift of M. Philips, both from New York University.
©2018 American Association for Cancer Research.
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