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Targeting the Microbiome to Enable Immunotherapeutic Efficacy in Pancreatic Carcinoma

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[Technical Report, Annual Report]

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The PRCRP Topic Area to be addressed is Pancreatic cancer. The PRCRP Military Relevance Focus Area is Gaps in cancer treatment. Pancreatic ductal adenocarcinoma PDA is characterized by immune-tolerance and resistance to immunotherapies. The microbiome has emerged as an important factor regulating health and disease. More specifically, we and other groups have shown that the microbiome has a pathogenic role in promoting the development of PDA and in mitigating response to therapy. Our recent published work indicates that the PDA-associated microbiome is markedly expanded by more than 1000-fold compared with the normal pancreas Pushalkar et al, Cancer Discovery 2018. Further, we found that mouse and human PDA-bearing hosts exhibit bacterial dysbiosis in the gut. Moreover, we found that the microbiome corrupts tumor immunity in PDA. Ablation of the microbiome in PDA was tumor-protective, upregulated expression of checkpoint receptors on T cells, and enabled efficacy for immunotherapy in mouse models of PDA. Based on these data, the microbiome is an attractive target in the treatment of PDA.

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  • Medicine and Medical Research

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[A, Approved For Public Release]