Pushalkar et al. show that the gut and pancreas microbiome in pancreatic ductal carcinoma (PDA) is distinct and stage-specific in mice and humans. The PDA microbiome activated M2-like tumor-associated macrophages via TLR2 and TLR5 signaling, leading to reduced T cell activation and enhanced oncogenesis. Bacterial ablation reduced MDSCs and increased M1-like macrophages within the tumor, resulting in increased infiltration and activation of T cells, and protection against tumor growth. Antibiotics synergized with anti-PD-1 to reduce tumor growth.

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.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. Cancer Discov; 8(4);1-14. (c)2018 AACR.

Author Info: (1) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (2) S. Arthur Localio Laboratory, Department of

Author Info: (1) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (2) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (3) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (4) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (5) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (6) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (7) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (8) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (9) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (10) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (11) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (12) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (13) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (14) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (15) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (16) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (17) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (18) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (19) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (20) National Gnotobiotic Rodent Research Center, University of North Carolina, Chapel Hill, North Carolina. (21) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (22) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (23) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (24) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (25) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (26) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (27) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (28) Department of Epidemiology and Health Promotion, NYU College of Dentistry, New York, New York. (29) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. (30) Department of Biology, Brooklyn College and the Graduate Center (CUNY), Brooklyn, New York, New York. (31) National Gnotobiotic Rodent Research Center, University of North Carolina, Chapel Hill, North Carolina. Department of Medicine, New York University School of Medicine, New York, New York. (32) Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York. george.miller@nyumc.org ds100@nyu.edu. S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. (33) S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, New York, New York. george.miller@nyumc.org ds100@nyu.edu. Department of Medicine, Microbiology, and Immunology, University of North Carolina, Chapel Hill, North Carolina.

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