Killer findings: How microbiota-derived metabolites enhance immunity – Australian research

University of Melbourne Associate Professor Sammy Bedoui, Immunology Laboratory Head at the Doherty Institute, and study leader, said this discovery could potentially improve cancer immunotherapy and immunisations as these treatments heavily rely on killer T cells.

Lead author of the study Dr Annabell Bachem, postdoctoral researcher at the Doherty Institute added that their discovery of the link between microbiota and killer T cells is a novel finding, as T cells in immune organs and microbiota exist in different locations and therefore don’t physically meet.
“Discovering that microbiota-derived metabolites that can not only diffuse into immune organs but also improve killer T cells is very exciting,“​ she said.

They said that their studies on mice, published in the journal immunity, revealed a previously unappreciated role for microbiota and their metabolites in ensuring that CD8+ T cells contract in a manner that supports long-term survival.

These observations have important implications for vaccination and immunotherapy, they claim. As it shows “not only that effective T-cell-based vaccines depend on correct antigen and adjuvant combinations but also that microbiota, diet, and the resulting exposure to SCFAs might affect the durability of protective memory CD8+ T cell responses.​”

Better survival

Associate Professor Sammy Bedoui said that a healthy and diverse microbiome and in particular its metabolites were crucial to produce the impact on the immune cells.
“We saw in our experiments that these microbiota-derived metabolites cause dramatic changes in the metabolism of the killer T cells; they change to use their energy in a more sustainable way, which is why they survive better,”​ Associate Professor Bedoui said.
“Our findings were also remarkable because these ‘survivor’ cells that were promoted by the microbiota and its metabolites are also the ones that have been shown to respond best to​
immunotherapy.”​
Currently only around 40 per cent of cancer patients respond favourably to immunotherapy.
“Having gained deeper insights into the molecular mechanisms of how the microbiota influence the immune system is really exciting. Supported by a research grant from Merck, we can now search for ways of harnessing this process to accelerate the development of new drugs that enhance the efficacy of cancer immunotherapy,”​ Professor Bedoui said.

The paper concludes: “​These observations have important implications for vaccination and immunotherapy. They suggest not only that effective T-cell-based vaccines depend on correct antigen and adjuvant combinations but also that microbiota, diet, and the resulting exposure to SCFAs might affect the durability of protective memory CD8+ T cell responses. ​

“This link between the microbiota and CD8+ T cells also sheds new light on the recent description that the relative abundance of certain SCFA-producing microbiota constituents is positively correlated with responsiveness to PD-1 blockade of patients with renal cancer or melanoma. ​

“Finally, our work has potential pharmacological relevance for adoptive T cell therapies using autologous T cells or chimeric antigen receptor (CAR) T cells, where an important aim is to promote memory potential in vitro prior to transfer into patients.”​

Source: Immunity​

“Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells”​

DOI:https://doi.org/10.1016/j.immuni.2019.06.002​

Authors: Sammy Bedoui, et al​