One of the important roles played by the gut microbiota involves directing maturation of the mammalian immune system, although the molecular basis involved is still being characterized. As a result, the intimate relationships between commensal microorganisms and the host system are subject to an increasing amount of research into managing immune-related conditions. In particular, the induction of intestinal CD8 T cells has been involved in host immune control of multiple infections and the efficacy of cancer immunotherapy.
A new study, led by Dr. Kenya Honda from the Keio University School of Medicine and RIKEN Center for Integrative Medical Sciences (Japan), has identified 11 bacterial strains from the human gut microbiota that enhance resistance to Listeria infection and improve the antitumor efficacy of checkpoint inhibitors in mice.
Cytotoxic CD8+ T cells are known to be effector lymphocytes involved in defending against cancerous cells and clearing intracellular pathogens. Mice housed under normal laboratory conditions harbored interferon-gamma-expressing CD8 T cells in their colons constitutively, whereas these cells were markedly decreased in mice born and raised in a germ-free environment.
The researchers aimed to identify whether gut bacteria might drive production of the subset of cytotoxic CD8+ T cells that produce the immunostimulatory protein interferon-gamma. A previous approach based on transferring fecal microbiota from healthy volunteers into germ-free mice was used, along with the subsequent analysis of bacteria subsets that grew in the murine colon. The researchers noted that tested strains were of low abundance in the original fecal samples, which might explain why they had not been identified previously as immune response modulators.
The authors isolated a mixture of 11 bacterial strains—including 7 Bacteroidales and 4 non-Bacteroidales species without virulence factors or toxins—from the sample that elicited the highest IFN-gamma CD8 T cell induction in mice and then transferred them to germ-free mice pretreated with antibiotics. Fragments from these 11 bacterial strains from the human gut microbiota were presented by dendritic cells to CD8+ T cells, leading to a boost in T-cell response characterized with accumulation of CD8+ IFN-gamma T cells in the cecum and colon that was apparent within the first week. The origin of these cells was unknown and, over time, they also accumulated in other locations beyond the gut.
The authors also explored the effects of this increase in CD8+ IFN-gamma T cells on defending against infection and on the effectiveness of a type of anticancer checkpoint-blockade immunotherapy treatment.
Mice that received the 11 bacterial strains from the human gut microbiota showed an increased capacity to fight Listeria monocytogenes infection, when compared with mice that did not receive them. Furthermore, the protective effects extended beyond the gut, as mice that received the combination of strains were also protected from L. monocytogenes infection of the spleen or liver.
Tanoue et al. also explored whether the administration of 11 defined bacterial strains enhanced the efficacy of immune checkpoint inhibitor treatment in two tumor models in which cancer cells were transplanted into the skin of mice. In line with findings observed with L. monocytogenes infection, the consortium of human bacteria led to an increase in CD8+ IFN-gamma T cells both at skin level and in the colon, with the T cells showing specificity for tumor antigens rather than for antigens in the mixture of administered bacteria. At the same time, the 11 strains also avoided colitis secondary to anticancer therapy. In contrast, CD8+ IFN-gamma T cells were not effective at inhibiting tumor growth in the absence of accompanying checkpoint-blockade treatment.
Although the origin of T cells in the transplanted tumors and in the colon is unknown, the authors propose that bacterial metabolites may be involved in boosting immune responses at distant body sites.
On the whole, this study identifies 11 strains of bacteria that reside in the guts of some healthy humans and which can boost immune responses mediated by CD8 T cells that fight infection and cancer. Now, these findings need to be translated to humans in order to explore the safety of the induction of CD8+ IFN-gamma T cells in patients receiving checkpoint-blockade therapy.
Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 2019. doi: 10.1038/s41586-019-0878-z.