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Researchers Propose Role For Microbes in Pancreatic Cancer Immune Features, Survival

NEW YORK – A team from the University of Texas MD Anderson Cancer Center, Texas Southern University, and Israel's Weizmann Institute of Science has uncovered potential ties between tumor microbes and pancreatic ductal adenocarcinoma (PDAC) — an effect suspected of reflecting differences in immune activity and immune infiltration.

"Our finding suggests that, independent of therapy, the PDAC tumor microbiome diversity and composition can influence immune infiltration that ultimately influences PDAC survival," senior corresponding author Florencia McAllister, a clinical cancer prevention researcher at the MD Anderson Cancer Center, and her colleagues wrote, suggesting that tumor microbe sequencing "could be used to stratify patients for adjuvant trials" down the road.

As they reported online today in Cell, the researchers used 16S ribosomal RNA sequencing to profile tumor microbial members in resected tumor samples from dozens of individuals with PDAC, uncovering enhanced microbial diversity in tumor samples from patients with longer-than-usual survival compared to more typical short-term survivors of the disease.

Along with such diversity differences, the team's results highlighted a microbial signature — marked by Bacillus clausii and Pseudoxanthomonas, Streptomyces, and Saccharopolyspora species — that appeared to coincide with, and predict, exceptional PDAC survival. On the other hand, another signature seemed to coincide with poor survival, prompting immunohistochemistry and mouse model experiments that looked at potential immune effects of the differing microbiomes documented in the PDAC patients.

"[W]e found that the tumor microbiome diversity has a powerful effect in determining the survival of PDAC patients," the authors wrote, noting that "tumor microbiome unique to [long-term survivors] may contribute toward shaping a favorable tumor microenvironment, characterized by the recruitment and activation of CD8+ T cells to the tumor milieu, and it might also be useful as a predictor of patients' outcomes."

With funding from the Pancreatic Cancer Moon Shot project at MD Anderson, the researchers focused on 22 "long-term survivors," a rare group of PDAC patients with overall survival times exceeding five years after surgical tumor resection. While roughly 9 percent of PDAC patients survive five years or longer, on average, individuals in the long-term survivor group had average survival times exceeding 10 years.

The team used 16S rRNA sequencing to profile microbial representatives in resected tumor samples from those long-term survivors, comparing them to tumor microbial members in resected tumor samples from 21 age-, gender-, and cancer stage-matched "short-term survivors" who succumbed to the disease within 1.6 years, on average.

The team validated its findings with 16S rRNA sequence data on tumor samples from another 15 patients who had survived at least 10 years and 10 short-term survivors (less than five years of survival) before using singleplex immunohistochemistry to identify more extensive CD8+ T cell infiltration in the tumor samples from patients with longer survival times.

Findings from fecal microbiota transplantation (FMT) experiments in mice, meanwhile, suggested fecal microbes from PDAC patients with shorter or longer survival could impact the microbial composition of mouse tumors, CD8+ T cell infiltration of those tumors, and T cell activity. There, researchers reported smaller tumors in the mice who got FMT from the long-term pancreatic cancer survivors — an effect that was muted in mice treated with antibodies that dialed down CD8+ T cell levels.

"Results of the FMT experiments represent a significant therapeutic opportunity to improve pancreatic cancer treatment by altering the tumor immune microenvironment," McAllister said in a statement. "There is promise here but we have a lot of work ahead."

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