The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression

Smruti Pushalkar, Mautin Hundeyin, Donnele Daley, Constantinos P. Zambirinis, Emma Kurz, Ankita Mishra, Navyatha Mohan, Berk Aykut, Mykhaylo Usyk, Luisana E. Torres, Gregor Werba, Kevin Zhang, Yuqi Guo, Qianhao Li, Neha Akkad, Sarah Lall, Benjamin Wadowski, Johana Gutierrez, Juan Andres Kochen Rossi, Jeremy W. HerzogBrian Diskin, Alejandro Torres-Hernandez, Josh Leinwand, Wei Wang, Pardeep S. Taunk, Shivraj Savadkar, Malvin Janal, Anjana Saxena, Xin Li, Deirdre Cohen, R. Balfour Sartor, Deepak Saxena, George Miller

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)403-416
Number of pages14
JournalCancer Discovery
Volume8
Issue number4
DOIs
StatePublished - Apr 2018

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Pushalkar, S., Hundeyin, M., Daley, D., Zambirinis, C. P., Kurz, E., Mishra, A., Mohan, N., Aykut, B., Usyk, M., Torres, L. E., Werba, G., Zhang, K., Guo, Y., Li, Q., Akkad, N., Lall, S., Wadowski, B., Gutierrez, J., Rossi, J. A. K., ... Miller, G. (2018). The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discovery, 8(4), 403-416. https://doi.org/10.1158/2159-8290.CD-17-1134