The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. It is curated by the Board of the European Association for Cancer Research (EACR).
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E. Riquelme et al., Cell Volume 178, Issue 4, 8 August 2019, Pages 795-806.e12
“Our study represents the first report to explore the influence of the tumor microbiome on clinical outcomes”
Summary of the findings
Pancreatic ductal adenocarcinoma (PDAC) is a disease with very prognosis. Most of PDAC patients have an overall survival (OS) shorter than 5 years. However, a minor subset of PDAC patients (9%) survive more than 5 years after surgery. The factors that determine such enigmatic long-term survival remain unknown. We investigated the role of the tumor microbiota and the immune system in influencing this long-term survival.
Using 16S ribosomal RNA gene sequencing, we analyzed the tumor microbiome composition in two independent cohorts of PDAC patients with long-term survival (LTS; OS >5 years) and short-term survival (STS; OS < 5 years). We found that alpha-diversity of the tumor microbiome was significantly higher in LTS patients compared with STS, suggesting the potential influence of tumor microbiome diversity in mediating pancreatic cancer progression. Furthermore, we identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. We also assessed the immune infiltrate infiltration by multiplex immunostaining. LTS tumors showed greater densities of CD3, CD8 T cells and granzyme B (GzmB)-positive cells compared with the STS tumors. Combining both results, we found a strong association between CD8 and GzmB tissue densities with microbiome diversity, suggesting that the tumor microbiome diversity may contribute to anti-tumor immune response by favoring recruitment and activation of CD8+ T cells.
We then aimed to learn where was the pancreatic tumors bacteria coming from and by comparing microbial composition of stools, pancreatic tumors and adjacent pancreatic area we did find a specific migration of bacteria from gut into tumors. This suggested that fecal microbial transplantation could modulate tumor microbiome and immune status, ultimately affecting tumor growth. Based on this premise, we then proceeded with human-into-mice fecal microbiota transplantation (FMT) from STS, LTS, and healthy controls onto mice that were then challenged with pancreatic tumors. Results from these experiments showed that the tumor immune activation status as well as tumor growth can be modulated by the gut-tumor microbial axis.
In short, our study demonstrates that PDAC microbiome composition, which partially migrated from the gut, influences the host immune response and potentially the natural course of the disease. The FMT experiments represent an immense therapeutic opportunity to manipulate the microbiome and the tumor immune microenvironment to improve the life expectancy of PDAC patients in whom few therapeutic options exist.
