Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes

Highlights•PDAC long-term survivors display high tumor microbial diversity and immunoactivation•A PDAC tumoral microbiome signature predicts PDAC long-term survival•The gut microbiome modulates the PDAC tumor microbiome landscape•Fecal microbial transplants can modulate tumors immunosuppression and growthSummaryMost 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-term survival (STS) and long-term survival (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.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJhYzRhNmZkNTc5YmU2ZjRkODc4YTZkNDEyZDQzOTU5ZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNzI5OTc2MDc1fQ.sGLbsGF-TuPx7Z-p-8rtSa3NNO0hKZeKPoEp0m_zNO15C8_qTCgG0Lhnr-ZsrgxbNzSNwtiV1Y_qH2K1sAkWmq69utDJ5XFoYWAzrsk8kqOgHCKW6gHqoX5UWJdlhwUnlVVnPqGoygCNX_jv2hSpRddTXnHcUmgDOUm0lnnbxcWV9HeoRsgniboBUD72x5GUpmO4vkfKcMyvltFknUtwBU1o9p199vDfx0XiALogOzc5SvwctGAI2fntZdJL0S9LKEESpSvSgdQ6AdF5ElEOnmAtyWXJNhgyrgSX7fViQS_JQ1DFf4rRXZn2s3_fw5eI3rNr6W9AW1hZStAAJBxDugDownload video (mp4, 20 MB)Graphical abstract