Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, chair of pathology, Oregon Health and Science University, Portland; Richard D. Press, MD, PhD, professor and director of molecular pathology, OHSU; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Sounak Gupta, MBBS, PhD, senior associate consultant, Mayo Clinic, Rochester, Minn.; Tauangtham Anekpuritanang, MD, molecular pathology fellow, Department of Pathology, OHSU; Hassan Ghani, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; and Fei Yang, MD, assistant professor, Department of Pathology, OHSU.

Tumor microbiome diversity 
and composition: influence on pancreatic cancer outcomes

November 2019—Pancreatic adenocarcinoma has a dismal prognosis, with a high incidence of relapse and a median overall survival of 24 to 30 months. Only nine percent of patients are alive five years after surgery. Genome-wide mutational landscape studies to decipher the factors that contribute to long-term survival have been futile. Recent studies in patients with melanoma and lung cancer have shown that the gut microbiota can mediate tumor responses to chemotherapy and immunotherapy, influencing overall outcome. Previous data (Balachandran, et al.) have shown that pancreatic adenocarcinoma (PDAC) tumors from long-term survivors harbor a high quantity of neoantigens with a profile similar to that of microbial epitopes. To further explore this concept, Riquelme, et al., performed a comprehensive analysis at the MD Anderson Cancer Center, in which they compared the tumor microbiome of PDAC patients with long-term survival (more than five years; average overall survival, 10.14 years) and short-term survival (less than five years; average overall survival, 1.62 years) using the 16S ribosomal community profiling method. The results revealed that the long-term survivors’ tumors had significantly higher intratumor microbiome diversity compared with the short-term survivors’ tumors. Furthermore, the long-term survivors’ tumors had a distinctive tumor microbiota signature that is enriched for specific bacterial taxa: Saccharopolyspora, Pseudoxanthomonas, and Streptomyces. Adding a fourth bacterial species, Bacillus clausii, which is also enriched in the long-term survivors’ tumors, created a microbiome signature that was strongly associated with long-term survivorship in PDAC patients. The same microbiota signature was also found to be predictive for long-term PDAC survival in an independent validation cohort from a geographically different medical center, Johns Hopkins Hospital. The area under the curve for predicting long-term survival was 97.51 and 99.17 percent in the discovery and validation cohorts, respectively, using the signature of the four bacterial species. To assess whether the gut microbiome could be modulated and in turn influence the intratumor microbiota and affect tumor growth, Riquelme, et al., conducted a series of experiments. First, the authors compared the microbiome of the PDAC tumor and adjacent normal tissue to that in matched stool samples and identified the presence of gut microbiome within the tumor, suggesting there is crosstalk between the human gut and the PDAC intratumor microbiota. Second, fecal microbial transplantation (FMT) studies were performed in mice that were subsequently challenged with PDAC implantation. Interestingly, the mice that received the FMT from the long-term survivor patients demonstrated a 70 percent reduction in tumor growth compared with the mice that received the FMT from the short-term survivor donors. The authors then assessed the role of the immune system in modulating tumor growth. They found that the long-term survivor patients had an immunoactivation profile with higher tissue density of CD8⁺ T cells and higher levels of serum cytokines than the short-term survivor patients. Similar findings were observed in the mice that received FMT from the long-term survivor patients. Bacterial ablation using short-term antibiotics or CD8⁺ T-cell depletion with neutralizing antibodies induced larger tumors in these mice. Statistical analysis revealed that CD8⁺ T-cell tissue density was strongly correlated with tumor microbiome diversity, the unique microbiome signature in long-term survivor patients, and the overall survival of PDAC patients. These results suggest that tumor microbiome diversity may contribute to anti-tumor immune response by favoring recruitment of CD8⁺ T cells to the tumor milieu and their activation. In summary, Riquelme, et al., identified a tumor microbial signature unique to pancreatic cancer long-term survival that could potentially be used as a predictive biomarker. Moreover, due to the gut-to-tumor microbial crosstalk, fecal microbial transplant can be considered a potential therapeutic option to create a favorable tumor microenvironment in pancreatic cancer patients.

Balachandran VP, Luksza M, Zhao JN, et al. Identification of unique neoantigen qualities in long-term pancreatic cancer survivors. Nature. 2017;551(7681):512–516.

Correspondence: Dr. Vinod P. Balachandran at balachav@mskcc.org

Riquelme E, Zhang Y, Zhang L, et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 2019;178(4):795–806.