Yet more on bugs and cancer

T-cells (red) on the attack

A Research Highlights piece in December’s Nature Reviews Cancer reports on another intriguing aspect of the interplay between our immune systems and the bugs we carry, namely how gut flora might influence the effectiveness of cancer immunotherapy.

Two international research groups set out to determine  whether the composition of the gut microbiome might influence the response to immunotherapy  directed against  PD-1, a so-called “immune checkpoint “ expressed by activated T cells and macrophages and which is exploited by cancer cells to switch off immune attack. Antibody-mediated blockade of the interaction between PD-1 and its ligand, PD-L1 can restore the anti-cancer response. The anti-PD-1 antibodies pembrolizumab and nivolumab (Opdivo® and Keytruda®, respectively) have proved their worth in the treatment of metastatic melanoma and a variety of other solid tumours.

Genetic analysis of faecal bacteria collected from cancer patients before and after anti-PD-1 immunotherapy found a correlation between gut bacteria diversity and the duration of progression-free survival in cancer patient after treatment.

A collaboration between US and French researchers found differences in the abundance of certain gut bacteria, with Faecalibacterium being enriched in melanoma patients responsive to anti‑PD1 therapy: Bacteroidales was enriched in those patients not responsive to immunotherapy. Differences were also found between responders and non-responders in regards to bacterial metabolism and the composition of immune cells found in the tumour microenvironment. Tumour-infiltrating “killer” T cells were more likely to be found in patients carrying an abundance of Faecalibacterium, while  immunosuppresive cells were more common in individuals carrying abundant Bacteroidales.

Another (again, predominantly American and French) research group found that the abundance of the gut bacterium Akkermansia muciniphila in non-small cell lung cancer and renal cancer patients correlated with a positive response to anti-PD-1 immunotherapy.

Both groups looked for possible mechanistic links between gut bacteria abundance and treatment response. When patient-derived gut bacteria were transplanted into germ-free mice, a variety of favourable effects on tumour growth and immune response were observed, including higher numbers of killer T-cells  and other, immune effector cells, along with changes in the expression of  T- cell receptors for key immune signalling molecules (“chemokines”).

The response to immunotherapy is difficult to predict and involves a variety of tumour factors (PD-L1 expression, tumour burden, degree of mutation) and host factors (immune system genetic makeup, T cell infiltration of the tumour). Analysis of the gut microbiome is unlikely to improve prediction of response, but preservation or manipulation of the gut microbiome through avoidance of antibiotic treatment prior to immunotherapy, or probiotic treatment to encourage “good” bacteria could conceivably translate into better and more sustainable response rates for at least some individuals.  

Photo credit : Rita Elena Serda.  National Cancer Institute \ Duncan Comprehensive Cancer Center at Baylor College of Medicine

Update added 3rd March 2018

Merck are in the process of recruiting for a study in which subjects will receive "faecal bacterial transplants" from individuals treated for melanoma and who have responded to PD-1 immune checkpoint inhibitor therapy. A further two gut microbiome-immuno-oncology clinical studies will also begin recruitment in 2018.

Oncologists tap the microbiome in bid to improve immunotherapy outcomes. Mullard, A. News & Views, Nature Reviews Drug Discovery. Published online 16th February 2018; doi:10.1038/nrd.2018.19. Subscription or purchase needed to access whole article. 

Microbes matter. Anna Dart. Nature Reviews Cancer,online December 8^th,  2017 doi:10.1038/nrc.2017.120

Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Gopalakrishnan, V et al.: Science, online November 2^nd, doi: 10.1126/science.aan4236.

Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Routy, B et al.  Science, online November 2^nd , doi: 10.1126/science.aan3706.