Tanoue et al. 2019. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature.

This is a summary of our DalMUG journal club discussion of this paper written by Jacob Nearing

Summary

This report by Tanoue et al., continues on with a developing story from 2018 where three independent studies showed that microbiome composition was linked to immunotherapy responses. In this report Tanoue et al., demonstrate a methodological pipeline for identifying a subset of gut microbes with desired immune modulation features. The characteristic that was of interest in this case was the induction of IFNy CD8 T cells. By pushing the microbiome composition of donors through a narrowing pipeline that consisted of various FMT experiments the researchers were able to find a consortium of 11 different bacterial strains (“11-mix”) that induced high systemic levels of IFNy CD8 T cells. This was of interest as this subset of cells is known for their ability to fight off intracellular pathogens as well as their ability to kill tumor cells. They demonstrate this by treating mice infected by Listeria monocytogenes with the 11-mix which protected them from infection. Furthermore they show that the 11-mix showed a significant increase in response to anti-PD1 therapy against a melanoma cancer model using MC38 cells. Results from this paper have directly led to an upcoming clinical trial by Vedanta Biosciences.

Points of Interest

• It was exciting to see that the 11-mix consortium showed such large effect sizes in the protection against Listeria monocytogenes infection and immunotherapy treatment.
• We were pleased to see that the genomes of the 21 strains identified in this paper have been sequenced and are publically available.
• The investigation of the immunological basis for the induction of CD8 T cells was very satisfying to read
• It was good to see that experiments for infection protection and immunotherapy response were done in SPF mice as it showed that this consortium may be clinically relevant
• We look forward to future studies that could determine what is so special about the 11-mix consortium and whether or not similar consortiums could also be found/designed.
• Finally we were excited to see that work from this report is being continued in a phase 1 trail that we will be closely following as results are reported.

Points of Confusion

• We were confused as to why only six donors were tested and how these individual donors were chosen. Although donor B seemed to have the smoking gun in terms of microbiome composition, it is unclear if more optimal microbiomes may exist for sampling.
• We would have been interested to see whether or not the composition of the outlier mouse that received FMT from donor E in Figure 1C had a similar composition as the mice that received FMT from donor B.
• We thought that disclosing the use of antibiotic pretreatment in SPF mice should have been included in the main results section of the paper as it could be misleading to readers.
• It was interesting to see that in Figure 4D the effect of 11-mix alone was similar to that of anti-PD-1 therapy. We would have liked to see this result in SPF that were not treated with antibiotics compared to SPF 11-mix mice.