Studies headed by researchers at the University of Texas (UT) MD Anderson Cancer Center suggest that a key difference between those few pancreatic cancer patients who survive for the long term, and the vast majority of patients whose disease quickly beats all treatment is the overall diversity and specific signature of bacteria that live on their tumors.

The study results also showed that transplanting stool samples—fecal microbiota transplantation (FMT)—from human long-term survivors (LTS) of pancreatic cancer into a mouse model of the disease changes the animals’ tumor microbiomes, and can help to reduce pancreatic cancer growth. The findings indicate that it may be possible to target the tumor microbiome as a therapeutic approach against pancreatic cancer. “Results of the FMT experiments represent a significant therapeutic opportunity to improve pancreatic cancer treatment by altering the tumor immune microenvironment,” said research lead Florencia McAllister, MD, assistant professor of clinical cancer prevention at MD Anderson. “There is promise here but we have a lot of work ahead.” McAllister, together with colleagues in the United States and Israel, describe their studies and results in Cell, in a paper titled, “Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.”

Most patients with pancreatic ductal adenocarcinoma (PDAC), which is the most common form of pancreatic cancer, have already progressed to late-stage disease by the time they are diagnosed, and so prognosis is “dismal,” with the five-year survival rate only about 9%, the authors wrote. Patients with earlier stage pancreatic cancer that can be surgically removed also have a high recurrence rate and survival averages at 24–30 months.

A very few pancreatic cancer patients are still alive more than five years after their surgery, but the factors that determine such “enigmatic” long-term survival aren’t known, the researchers continued. While research to date hasn’t identified a consistent genetic background that might predict long-term survival, studies have hinted that “microbial host factors, independent of the genomic composition of the tumor, may determine tumor behavior and patient outcomes,” the authors continued.

In fact, previous studies in melanoma have suggested that gut bacteria can influence immune system activation and tumor response to different therapies. The indication from multiple studies is that modulating the gut and/or tumor microbiome could represent a novel strategy to sensitize tumors to treatment. What isn’t known is whether that potential may also extend to pancreatic cancer. “Despite all this knowledge, the composition of the human PDAC microbiome that contributes favorably or adversely to the natural history of pancreatic cancer remains incompletely studied,” the researchers noted. It’s a significant unmet need, they point out, as most chemotherapy and immunotherapies that might work in other cancers tend not to work well against PDAC.

To look at this more closely the researchers used 16s rRNA gene sequencing to compare the tumor microbiomes of pancreatic tumor samples from long-term survivors (LTS), and short-term survivors (STS) of pancreatic cancer. The LTS had undergone surgery and then survived more than five years (average 10.1 years after their surgery). In contrast, the STS patients died within five years of surgery, with survival averaging at just 1.6 years.

The analyses included 22 LTS and 21 STS patients (the discovery cohort) from the UT MD Anderson Cancer Center, and a separate validation cohort of 15 LTS patients and 10 STS patients from the Johns Hopkins Hospital. Stratifying the MD Anderson patients just by tumor microbiome diversity indicated that those with high diversity had median survival of 9.66 years, while those with low diversity had median survival of 1.66 years. These results were independent of factors that may have affected the tumor microbiome, such as prior treatment, body mass index, or antibiotic use.

In both the MD Anderson and Johns Hopkins patient cohorts there was also a link between survival and relative abundance of specific microbial communities. The tumor microbiomes of LTS patients had high relative abundance of Pseudoxanthomonas, Saccharropolyspora, and Streptomyces bacteria. The presence of these three classes of bacteria, plus the species Bacillus clausii, was highly predictive of better patient outcome.

“We hypothesized that tumoral bacteria has the ability to shape the immune tumor microenvironment that can influence the natural history of the cancer,” the team noted. Immunohistochemical analyses did show higher numbers of T cells, including cancer cell-killing CD8+ T cells, in the tumors of LTS patients from both cohorts. Further tests identified a strong correlation between immune cell infiltration and the microbiome diversity of the tumors, and indicated that immune infiltration and activation of T cells was associated with the three enriched bacterial types identified in the LTS tumor microbiota. “These findings suggest that the tumor microbiome diversity and the presence of these three genera in the tumor may contribute to the anti-tumor immune response by favoring recruitment and activation of CD8+ T cells,” they stated.

The next step was to investigate whether changing the tumor microbiome composition would have any effect on pancreatic cancer progression and survival. This would have to be done indirectly. “You cannot modulate the tumor microbiome directly, but you can modulate the gut microbiome, and if there’s cross-talk between the gut and the tumor microbiomes, you could change the tumor microbiome indirectly,” McAllister explained.

The researchers’ comparison of bacteria in the gut, tumors, and healthy adjacent tissue of three surgically resected pancreatic cancer patients indicated that gut microbiota could colonize the pancreatic tumors. “Because the bacterial composition found in normal adjacent tissue differs from that found in the tumor, it suggests that the tumor microbiome might be unique,” the team stated. “This data suggests that the gut microbiota has the capacity to specifically colonize pancreatic tumors.”

To investigate this concept the researchers investigated the effects of transplanting fecal microbiota from advanced human pancreatic cancer patients into mice. They found that while the donor microbiome represented about 5% of the resulting tumor microbiome, about 70% of the overall tumor microbiome was also altered by the transplant. “Now we know you can completely change the bacterial composition of the tumor microbiome by doing FMT,” McAllister said.

Florencia McAllister, MD [MD Anderson Cancer Center]
The next stage was to carry out and compare the effects of FMT from advanced pancreatic patients, LTS patients with no evidence of disease (LTS-NED patients), and healthy controls, into mice. The animals also received tumor implants, and were assessed five weeks later. The results showed that the FMT-recipient mice that had received FMT from patients with advanced disease had much larger tumors than those receiving FMT from long-term survivors (70% smaller average size) or healthy controls (50% smaller average size).

“We observed a significant reduction in tumor growth in mice that received FMT from LTS-NED donors compared with the mice transplanted with stools from STS donors or HC donors,” they wrote. “These results suggest that gut/tumor bacteria from patients who had PDAC and survived long-term may have a protective effect against tumors.” Interestingly, tumors from mice that had received an FMT from STS patients were larger than those in mice who received a fecal transplant from the healthy controls, “suggesting that PDAC-associated gut/tumor bacteria may exert a tumor-promoting effect.”

To confirm that the effects of FMT on tumor growth were related to the bacteria, one group of animals was given a short course of antibiotics in addition to their LTS-NED fecal transplant. These animals developed larger tumors than mice receiving just the LTS-NED fecal transplant and no antibiotics. “These data indicate that bacteria ablation can decrease the anti-tumoral efficacy induced by LTS-NED FMT, which validates the central role of bacteria,” the scientists claimed.

Immune profiling in addition showed that the mice receiving FMT from long-term survivors had significantly higher numbers and greater activation of CD8+ T cells compared with animals in the other two groups. Mice that received an FMT from advanced-stage patients had increased regulatory T cells and myeloid-derived suppressor cells, both of which suppress the immune response. Depleting T cells in a group of mice treated with the long-term survivor FMT completely blocked the anti-tumor effect of the transplant.

“Our study represents the first report to explore the influence of the tumor microbiome on clinical outcomes,” the authors stated. “In conclusion, we found that the tumor microbiome diversity has a powerful effect in determining the survival of PDAC patients.” The results suggest that the tumor microbiomes of pancreatic patients could represent a useful prognostic tool, but may also represent “… an immense therapeutic opportunity to manipulate the microbiome to improve the life expectancy of PDAC patients in whom few therapeutic options exist.”

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