期刊
CANCER DISCOVERY
卷 8, 期 4, 页码 403-416出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-1134
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资金
- NIH [CA206105, CA168611, CA155649, DE025992, CA180277, CA175794, P40 OD010995, P30 DK034987]
- Department of Defense Peer Reviewed Medical Research Program
- Lustgarten Foundation
- Panpaphian Association of America
- National Pancreas Foundation
- Crohn's and Colitis Foundation of America
- NYU Provost Office Mega Grant Seed Fund Initiative
- Irene and Bernard Schwartz Fellowship in GI Oncology
- Cancer Center Support Grant [P30CA016087]
- National Center for the Advancement of Translational Science (NCATS) [UL1 TR000038]
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. (C) 2018 AACR.
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