gut microbiome, melanoma, PD-1

Gut Microbiome Influences Response to PD-1 Targeted Immunotherapy

Although immune checkpoint inhibitors targeting the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and PD-1 signaling pathways induce long-lasting tumor responses in patients with melanoma, responses to these agents are often heterogeneous and not durable. The clinical and patient characteristics influencing response to immune checkpoint inhibitors are not well understood. The importance of the gut microbiome in the development and function of the immune system is well-known, and several studies have demonstrated the impact of the gut microbiome on anti-tumor immune responses. Furthermore, in preclinical models the gut microbiome has been shown to modulate responses to immune checkpoint inhibitors.

To better understand the role of microbiome in response to immune checkpoint blockade, a prospective study examined the composition of the oral and gut microbiome in 112 patients with advanced melanoma before and after treatment with PD-1 inhibitors. While there were no major differences in the oral microbiome among responders and nonresponders, patients who responded to anti–PD-1 therapy had significant differences in their gut microbiomes compared to patients who did not respond. Responders had significantly higher alpha diversity (P<.01) and greater abundance of bacteria in the Ruminococcaceae family, including Faecalibacterium (P<.01), than patients who did not respond. Patients with high microbiome diversity had improved progression-free survival (PFS) compared to patients with intermediate diversity (P = .02) or low diversity (P = .04). Likewise, abundance of Faecalibacterium was associated with prolonged PFS (P = .03), while abundance of Bacteroidales, found predominantly in the gut microbiome of nonresponders, was associated with shortened PFS (P = .05).

Functional genomic profiling of the gut microbiome in responders versus nonresponders revealed an enrichment of anabolic pathways influencing host immunity in patients responding to PD-1 inhibitors. Systemic and antitumor immune responses were also enhanced in these patients. These findings were confirmed with fecal microbiome transplant to germ-free mice. Mice receiving fecal transplant from responders had significantly reduced tumor growth compared to mice receiving transplant from nonresponders (P = .04).

The authors concluded that these results support a role for the gut microbiome in modulating responses to PD-1 inhibitors in patients with melanoma, and identified a “favorable” microbiome as containing high diversity and abundance of Ruminococcaceae/Faecalibacterium. Strategies aimed at modulating the gut microbiome of patients receiving PD-1 inhibitors should be investigated in clinical trials.