Recent research has pointed to the role of gut microbiota-host interactions in the effectiveness of immunotherapeutic agents (here; here). However, little is known regarding the potential role of the gut microbiota in the immune-mediated effects of drugs used as cancer immunotherapy.
A review by Dr. Christian Jobin, from the Department of Medicine, Department of Infectious Diseases and Immunology, and Department of Anatomy and Cell Biology at University of Florida (Gainesville, Florida, USA), discusses how cancer immunotherapies could be used with more precision when considering gut microbiota-mediated interactions with the immune system in the efficacy of these cancer drugs.
Jobin addressed in the review 3 recent studies (here; here; here) providing evidence that it may be beneficial to stratify patients into responders and non-responders to immunotherapy on the basis of the composition of their intestinal microbiomes.
Targeting molecules that inhibit the effector T lymphocyte response -called immune checkpoints- in order to enhance adaptive immune responses against tumour cells is emerging as a therapy for fighting cancer. Specifically, targeting the programmed cell death protein 1 (PD-1)-PD-1 ligand 1 (PD-L1) axis has emerged as a promising approach to cancer therapy in solid tumours.
As the gut microbiota is involved in modulating immune responses, the researchers sought to investigate whether it may play a role in enhancing responses to therapies focused on targeting immune checkpoints. Gopalakrishnan et al. found that patients responding to anti-PD-1 therapy had a high relative abundance of Faecalibacterium at baseline, whereas non-responding patients had a high relative abundance of bacteria of the order Bacteroidales in their faeces. Besides this, bacterial diversity and abundance of Faecalibacterium and Bacteroidales in faecal samples were the strongest predictors of anti-PD-1 therapy response.
Furthermore, Matson et al. found that patients responding to anti-PD-1 therapy had – at baseline – an increased abundance of 8 microbial species, including Bifidobacterium longum. In this line, a previous study discovered that in mice oral administration of Bifidobacterium alone improved tumour control to the same degree as PD-L1-specific antibody therapy.
Finally, Routy et al. found that antibiotic exposure during the course of cancer therapy correlated negatively with response to anti-PD-1 treatment in patients with non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma. Besides this, there was an increase in faecal relative abundance of Akkermansia muciniphila at the time of diagnosis in patients showing favourable outcomes to anti-PD-1 treatment. These results support the findings of Gopalakrishnan et al. and Matson et al., suggesting that gut microbiota alteration with loss of specific bacterial populations may interfere with the efficacy of immune-related cancer therapeutic drugs.
In all three studies, faecal microbiota transfer (FMT) from responder patients to tumour-bearing mice improved responses to anti-PD-1 therapy and correlated with increased antitumour CD8+ T cells -a kind of effector T lymphocyte involved in immune responses against tumours-. However, mice receiving FMT from non-responder patients did not respond to anti-PD-1 therapy, and tumours had a high density of CD4+ Treg cells, which are immunosuppressive and exhibit a poor antitumour response. Interestingly, Routy et al. found that introduction of A. muciniphila to mice receiving human non-responder FMT reversed the low response to PD-1 treatment. These data open the possibility for manipulation of the gut microbiota to shift patients that are non-responsive to cancer therapy based on immune checkpoint blockade into responders.
To sum up, the gut microbiota enrichment in certain microbial taxa including Akkermansia, Faecalibacterium and Bifidobacterium correlates with response to anti-PD-1 treatment in patients with metastatic melanoma and patients with non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma. These data suggest that gut microbiota is a key factor when assessing cancer therapeutic intervention. In order to investigate whether microbiota-focused research could translate into new therapeutics, a better characterization of the influence of the gut microbiota in cancer patient responses to immunotherapy is needed.
Jobin C. Precision medicine using microbiota. Science. 2018; 359(6371):32-4. doi: 10.1126/science.aar2946.
Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018; 359(6371):91-7. doi: 10.1126/science.aan3706.
Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371):97-103. doi: 10.1126/science.aan4236.
Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018; 359(6371):104-8. doi: 10.1126/science.aao3290.
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