Tuning the Microbiome Improves Melanoma Immunotherapy Response

Bacteria that live in the human digestive tract can influence how cancer responds to immunotherapy, opening a new avenue for research to improve treatment, a team led by researchers at The University of Texas MD Anderson Cancer Center reports in the journal Science.  Findings from the new study – (“Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients”) could provide a new avenue for research to improve treatment.

Patients with metastatic melanoma treated with anti-PD1 checkpoint blockade have their disease controlled longer if they have a more diverse population of bacteria in the gut or an abundance of certain types of bacteria, according to the MD Anderson team’s analysis of fecal samples to assess patients’ gut microbiomes. Previous research has shown that a person’s microbiome is a modifiable risk factor that can be targeted by diet, exercise, antibiotic or probiotic use, or transplantation of fecal material.

“You can change your microbiome, it’s really not that difficult, so we think these findings open up huge new opportunities,” explained senior study investigator Jennifer Wargo, M.D., associate professor of surgical oncology and genomic medicine at MD Anderson. “Our studies in patients and subsequent mouse research really drive home that our gut microbiomes modulate both systemic and antitumor immunity.”

Immune checkpoint blockade drugs that assist the body’s immune system to attack cancer cells help around 25% of metastatic melanoma patients, and those responses are not always durable. To assess the impact of the microbiome on these therapies, Dr. Wargo and her colleagues analyzed buccal swabs—tissue samples from inside the cheek—and fecal samples of patients treated with anti-PD1 therapy that blocks the PD1 protein on T cells, which acts as a brake on the immune system. They conducted 16S ribosomal RNA (rRNA) and whole-genome sequencing to determine diversity, composition, and functional potential of the buccal and fecal microbiomes.

Interestingly, while the team found no substantial differences in response or progression based on buccal samples, analysis of fecal samples of 30 patients who responded to treatment and 13 who did not tell a different story.

“We examined the oral and gut microbiome of melanoma patients undergoing anti-PD-1 immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders (R) versus non-responders (NR),” the authors wrote. “Analysis of patient fecal microbiome samples (n=43, 30R, 13NR) showed significantly higher alpha diversity (p<0.01) and relative abundance of Ruminococcaceae bacteria (p<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and anti-tumor immunity in responding patients with a favorable gut microbiome, as well as in germ-free mice receiving fecal transplants from responding patients.”

The researchers observed that patients with a higher diversity of bacteria in their digestive tract had longer median progression-free survival (PFS), defined at the time point where half of studied patients have their disease progress. While the patient group with high diversity had not reached median PFS (more than half had not progressed), those with intermediate and low diversity had median PFS of 232 and 188 days, respectively.

Additional analysis showed that responding patients with elevated levels of the beneficial Clostridiales/Ruminococcaceae had greater T-cell penetration into tumors and higher levels of circulating T cells that kill abnormal cells. Those with abundant Bacteriodales had higher levels of circulating regulatory T cells, myeloid-derived suppressor cells, and a blunted cytokine response, resulting in dampening of antitumor immunity.

To investigate causal mechanisms, the team transplanted fecal microbiomes from responding patients and nonresponding patients via fecal microbiome transplant (FMT) into germ-free mice. Those receiving transplants from responding patients had significantly reduced tumor growth as well as higher densities of beneficial T cells and lower levels of immune suppressive cells. They also had better outcomes when treated with immune checkpoint blockade.

Though the researchers were excited by their findings, they noted that there is still much to learn about the relationship between the microbiome and cancer treatment, urging people not to attempt self-medication with probiotics or other methods.