TY - JOUR
T1 - The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression
AU - Pushalkar, Smruti
AU - Hundeyin, Mautin
AU - Daley, Donnele
AU - Zambirinis, Constantinos P.
AU - Kurz, Emma
AU - Mishra, Ankita
AU - Mohan, Navyatha
AU - Aykut, Berk
AU - Usyk, Mykhaylo
AU - Torres, Luisana E.
AU - Werba, Gregor
AU - Zhang, Kevin
AU - Guo, Yuqi
AU - Li, Qianhao
AU - Akkad, Neha
AU - Lall, Sarah
AU - Wadowski, Benjamin
AU - Gutierrez, Johana
AU - Rossi, Juan Andres Kochen
AU - Herzog, Jeremy W.
AU - Diskin, Brian
AU - Torres-Hernandez, Alejandro
AU - Leinwand, Josh
AU - Wang, Wei
AU - Taunk, Pardeep S.
AU - Savadkar, Shivraj
AU - Janal, Malvin
AU - Saxena, Anjana
AU - Li, Xin
AU - Cohen, Deirdre
AU - Sartor, R. Balfour
AU - Saxena, Deepak
AU - Miller, George
N1 - Publisher Copyright:
©2018 American Association for Cancer Research.
PY - 2018/4
Y1 - 2018/4
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-17-1134
DO - 10.1158/2159-8290.CD-17-1134
M3 - Article
C2 - 29567829
AN - SCOPUS:85047056415
SN - 2159-8274
VL - 8
SP - 403
EP - 416
JO - Cancer Discovery
JF - Cancer Discovery
IS - 4
ER -