Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less
than 5-years, but a minor subset survives longer. Here, we dissect the role of the
tumor microbiota and the immune system in influencing long-term survival. Using 16S
rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients
with short and long-term survival (STS, LTS). We found higher alpha-diversity in the
tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature
(Pseudoxanthomonas/Streptomyces/Saccharopolyspora/Bacillus clausii) highly predictive
of long term survivorship in both discovery and validation cohorts. Through human-into-mice
Fecal Microbiota Transplantation (FMT) experiments from STS, LTS or control donors,
we were able to differentially modulate the tumor microbiome and affect tumor growth
as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome
composition, which cross-talks to the gut microbiome, influences the host immune response
and natural history of the disease. The distinct tumor microbiome from pancreatic
cancer long-term survivors can be used to predict PDAC survival in humans, and transfer
of long-term survivor gut microbiomes can alter the tumor microbiome and tumor growth
in mouse models.