The fine line between human health and disease can be driven by the interplay between host and microbial factors. This “metagenome” regulates cancer initiation, progression, and response to therapies. Besides the capacity of distinct microbial species to modulate the pharmacodynamics of chemotherapeutic drugs, symbiosis between epithelial barriers and their microbial ecosystems has a major impact on the local and distant immune system, markedly influencing clinical outcome in cancer patients. Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes. Future strategies of precision medicine will likely rely on novel diagnostic and therapeutic tools with which to identify and correct defects in the microbiome that compromise therapeutic efficacy.
Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer.
Science , this issue p. [91][1], p. [104][2], p. [97][3]; see also p. [32][4]
Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila . Oral supplementation with A. muciniphila after FMT with nonresponder 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 tumor beds.
[1]: /lookup/doi/10.1126/science.aan3706
[2]: /lookup/doi/10.1126/science.aao3290
[3]: /lookup/doi/10.1126/science.aan4236
[4]: /lookup/doi/10.1126/science.aar2946
Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer.
Science , this issue p. [91][1], p. [104][2], p. [97][3]; see also p. [32][4]
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy ( n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples ( n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity ( P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family ( P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
[1]: /lookup/doi/10.1126/science.aan3706
[2]: /lookup/doi/10.1126/science.aao3290
[3]: /lookup/doi/10.1126/science.aan4236
[4]: /lookup/doi/10.1126/science.aar2946
