Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients

Abstract

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.

Anti-PD1 in the wonder-gut-land

“…Wargo's group (MD Anderson Cancer Center, Houston, Texas, USA) explored the role of oral and gut microbiome in anti-PD1-treated melanoma patients by 16S rRNA gene sequencing [8]. The oral microbiome did not reveal differences between R and NR patients.…”

The gut microbiota and immune checkpoint inhibitors

“…Through comparing fecal samples from 112 MM patients taking anti-PD-1 Ab therapies, Wargo and colleagues found that responders had a significantly higher abundance of commensals of the Clostridales order and the Bacteroidales order, belonging to the Firmicutes phylum and Bacteroidetes phylum respectively. 38 Even though there was a clear difference in the cancer types studied between this publication and the 2017 publication by Zitvogel and colleagues, there were key similarities between the microbial profiles associated with response. Therefore, the species of commensal bacteria found essential for response may have little to do with the type of cancer which anti-PD-1 Ab targets.…”

“…35 , 36 A study by Herold and colleagues in December 2017 found systemic immune activation in humanized mice models given anti-CD3 mAb in combination with antibiotics, shown through elevated numbers of effector T-cells and IFN-γ, decreased production of IL-10, and the presence of anti-nuclear antibodies. 35 While there are other investigations demonstrating that gut dysbiosis, or a microbial imbalance or modification in the host gut, may counteract the effects of both immunosuppressive 35 and immunostimulatory drugs, 3 , 23 , 27 , 37 , 38 it may be that microbiota have a more potent or direct interaction with the immune checkpoint drugs rather than the immunomodulatory cells involved per se. All in all, these apparent contradictions reinforce that the function and mechanisms by which commensal bacteria communicate with the immune system are poorly understood and remain a fascinating challenge for prospective researchers.…”

“…Comparable to what was discovered in their 2015 publication, the authors measured an increase in stool richness, at the metagenomics species level, of the NSCLC and RCC patients after two months since their first injection of anti-PD-1 Ab. Moreover, a response to anti-PD-1 Ab has been shown to be associated with significantly higher alpha diversity of gut microbiota 38 and interestingly, increased levels of CTLA-4 hi PD-1 hi CD8+ T-cells. 25 Corresponding proportions are thus suggestive of a situational positive feedback mechanism where TILs or other systemic lymphocytes signal the proliferation of certain bacteria or possibly enrich the ecosystem in the gut to establish a more tolerable living environment for the gut microbiome.…”

Management of metastatic esophagogastric junction adenocarcinoma

“…Recent reports suggested that host microbiome and tumor and stromal genomic profiles may be related with response to immune checkpoint blockade [9,10] . The diversity and abundance of specific bacterial species in the oral and fecal microbiome enhanced systemic and antitumor immunity [43,44] . For example, in the patients with advanced tumor who received immunotherapy, the use of antibiotics caused poor prognosis.…”