According to a new study, the cancerous pancreas in mice and humans harbours an abundant microbiota that promotes immune suppression and oncogenesis.
Few studies have established a link between the gut microbiota and carcinomas in organs separate from the gastrointestinal tract. “In pancreatic ductal adenocarcinoma (PDAC), we previously reported that activation of pattern recognition receptors accelerates tumorigenesis via induction of innate and adaptive immune suppression,” explains author Mautin Hundeyin. “Therefore, we hypothesized that microbial dysbiosis can drive PDAC progression by promoting immune tolerance and targeting the microbiome can reverse this process.”
Using 16 S ribosomal RNA fluorescent probes and quantitative PCR, a 1,000-fold increase in intrapancreatic bacteria was found in human PDAC compared with normal pancreatic tissue. Select bacteria were increased in PDAC compared with the gut and were found to translocate via the pancreatic duct. “This was an interesting finding as the pancreas has traditionally been considered a sterile organ,” says Hundeyin.
In preinvasive and invasive mouse models of PDAC, bacterial ablation using germ-free mice or antibiotics was shown to protect against PDAC growth and was associated with immunogenic reprogramming of the tumour microenvironment. The decrease in select Toll-like receptor activation on monocytic cells led to increased tumour-protective M1 macrophage polarization, which promoted infiltration and activation of T helper cells and cytotoxic T cells.
Bacterial ablation also upregulated T-cell PD1 expression, suggesting an approach that could synergize with checkpoint-based immunotherapy. “Based on this finding, we are starting a clinical trial where patients with locally advanced PDAC will receive antibiotics and pembrolizumab prior to resection,” concludes Hundeyin. The data also suggest that elements of the microbiota might be useful in PDAC diagnosis.
Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018)
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Dickson, I. Microbiome promotes pancreatic cancer. Nat Rev Gastroenterol Hepatol 15, 328 (2018). https://doi.org/10.1038/s41575-018-0013-x
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