Gut Bacteria Can Affect Patient Responses to Anti-PD1 Immunotherapy

Resistance to immune checkpoint inhibitors can be attributed to abnormal gut microbiome composition

Two papers published on 5 January 2018 in Science point out on importance of gut flora for efficacy of PD-1-based immunotherapy. In particular, the first paper shows that antibiotic consumption is associated with poor response to PD-1 blockade. The investigators profiled samples from patients with epithelial tumours (lung and renal) and found that non-responding patients had low levels of the bacterium Akkermansia muciniphila. Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. In second paper the authors studied melanoma patients treated with PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Non-responders had an imbalance in gut flora composition, which correlated with impaired immune cell activity.

Primary resistance to immune checkpoint inhibitors targeting the PD-1/PD-L1 axis can be attributed to abnormal gut microbiome composition. Routy et al.1 showed that antibiotics inhibited the clinical benefit of immune checkpoint inhibitors in patients with advanced cancer. Fecal microbiota transplantation from cancer patients who responded to immune checkpoint inhibitors into germ-free or antibiotic-treated mice ameliorated the antitumour effects of PD-1 blockade, whereas fecal microbiota transplantation from non-responding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to immune checkpoint inhibitors and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after fecal microbiota transplantation with non-responder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumour beds.

In second paper, Gopalakrishnan et al.2 emphasize that preclinical mouse models suggest that the gut microbiome modulates tumour response to checkpoint blockade; however, until now this has not been well-characterised in human cancer patients. They examined the oral and gut microbiome of melanoma patients treated with anti–PD-1 immunotherapy. Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus non-responders. Analysis of patient fecal microbiome samples showed significantly higher alpha diversity and relative abundance of bacteria of the Ruminococcaceae family in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumour immunity in responding patients with a favourable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients.

These data have important implications for the treatment of patients with immune checkpoint inhibitors. 

References

1. 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):91-97. DOI: 10.1126/science.aan3706 

2.  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