Notebook:A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

Recently, Dr. Takeshi Tanoue et al report relationship between CD8 T-cells and anti-cancer immunity. This paper was published on Nature volume 565, pages600–605 (2019)

Dysbiosis of commensal microbiota can contribute to cancer onset, progression and therapy response through effects on anti-tumor immunity1-4.The currently studies have now advanced our understanding of local microbiota immunomodulation and gaveustheinsight into the potential of manipulated the microbial composition could transform treatment strategies for patients with cancer.

Using a genetically engineered mouse model of human lung adenocarcinoma, with KrasG12D mutation and Trp53 deletion in lung epithelial cells 5, compared tumor initiation and progression in germ- free (GF) and specific pathogen- free (SPF) control conditions, and the results revealedthat both tumor growth and burden were decreased in GF mice compared with SPF mice. There was expansion of the total bacterial burden as well as limited bacterial diversity in tumor-bearing SPF mice in contrast to non-tumor-bearing SPF controls by analysing the bacterial composition from the bronchoalveolar lavage fluid of mice.

The tumor-associated γδ T cells displayed a unique gene expression signature distinguished by strong expression of effector molecules with the potential to stimulate tumor- promoting inflammation and tumor cell proliferation 6. Starting with human faecal samples from six healthy volunteers orally administered to GF mice, a sequence of selection steps was applied to obtain mice colonized in the intestines with human microbiota enriched in IFNγ+CD8+T cells- inducing species. From these mice, a mixture of 11 bacterial strains was selected on the basis that its inoculation into GF mice enhanced IFNγ+CD8+T cell frequency to the largest extent. Importantly, the 11-strain mixture could also inhibit tumor growth even without anti- PD1 treatment.                                                             

These findings provide an example of rare species that can enhance anti-microbial and anti-tumor immunity with a potentially large effect size. The contribution of such species may be underestimated by conventional, sequence-oriented microbiome analyses. Those isolated strains have great bio-therapeutic potential and could be broadly applicable to enhancing the treatment of disease like cancer and infectious, as they are severely underrepresented in the gut microbiota of most individuals.

Reference:

1. Mimee, M., Citorik, R. J. & Lu, T. K. Microbiome therapeutics — advances and challenges. Adv. Drug Deliv. Rev. 105, 44–54 (2016).

2. Kim, S., Covington, A. & Pamer, E. G. The intestinal microbiota: antibiotics, colonization resistance, and enteric pathogens. Immunol. Rev. 279, 90–105 (2017).

3. El Hage, R., Hernandez-Sanabria, E. & Van de Wiele, T. Emerging trends in“smart probiotics”: functional consideration for the development of novel health and industrial applications. Front. Microbiol. 8, 1889 (2017).

4. Blander, J. M., Longman, R. S., Iliev, I. D., Sonnenberg, G. F. & Artis, D. Regulationof inflammation by microbiota interactions with the host. Nat. Immunol. 18, 851–860 (2017).

5. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

6. Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).