Pancreatic cancer: Targeting bacteria in pancreas may be key to treatment

Bacteria in the pancreas may promote pancreatic cancer by suppressing the immune system, according to a study published in Cancer Discovery. In addition, targeting the microbiome of the pancreas may make immunotherapy effective against pancreatic cancer.

The study, led by Smruti Pushalkar, PhD, from the New York University College of Dentistry, evaluated bacterial imbalance and the progression of pancreatic ductal adenocarcinoma (PDA) in mice and human tissue. The research team found that eliminating certain bacteria slowed the growth of pancreatic cancer, reversed immune suppression, and upregulated the immune checkpoint protein PD1.

Prior research has shown that the microbiome contributes to oncogenesis in a number of intestinal tract malignancies, such as laryngeal, esophageal, gastric, and colorectal cancers, as well as in primary liver cancer. However, the relationship between PDA and the microbiome of the gut, which is remote from the pancreas, has not been established.

The investigators found that the bacterial load was distinct in pancreatic tumor samples from patients with PDA when compared with pancreatic tissue from healthy individuals. They also compared fecal samples from patients with PDA and from healthy individuals and found that the bacterial composition of cancer patients was significantly higher and more diverse from that of the healthy group.

Gene sequencing of PDA tumors from 12 patients revealed that the most common strains of bacteria found in all pancreatic cancer patients were Proteobacteria (45%), Bacteroidetes (31%), and Firmicutes (22%).

In mice, two bacteria associated with mouse chow were among the most abundant organisms found in the pancreas, which suggested translocation from the gut to the pancreas.

Eliminating these bacteria using antibiotics slowed the progression of pancreatic cancer and lowered the tumor burden by about half. This process also affected T-cell differentiation, leading to increased T-cell infiltration into the tumor and reduction in myeloid-derived suppressor cell (MDSC) population. Antimicrobial treatment also resulted in increased expression of PD1 on CD4+ and CD8+ T cells within the tumors.

Reintroducing bacteria in mice treated with antibiotics reversed the tumor protection and reduced the immunogenicity of the tumors, suggesting that the microbiome regulates immunogenicity in PDA.

The researchers also found that combining antimicrobial treatment with an anti-PD1 immunotherapy resulted in enhanced CD4+ and CD8+ T-cell activation in mice, suggesting that such a combination is a potential treatment option for PDA.

To determine why PDA progresses at variable rates, the researchers prospectively collected fecal specimens from mice, separated them based on rate of progression, and compared microbial phenotypes. Results showed that bacterial communities are distinct between early and advanced PDA.

The investigators suggested that, although prospective studies are needed, it is possible that antibiotics may be useful as a preventative measure for high-risk patients and probiotics may have a potential role in mitigating the risk of PDA.

“Our data suggest that elements of the microbiome may be useful in early diagnosis and risk stratification,” the authors concluded. “Further, microbial-targeted therapies may reduce risk in pre-invasive disease and may be used as an adjuvant to standard therapies or in synergy with checkpoint-directed immunotherapy in invasive disease.”

To read more about this study, click here.