The microbiome has become an area of intense interest for many health-related reasons. Add to this list the potential for a positive or a negative effect on responsiveness to immunotherapy. Gut microbiota that were more diverse, and that contained an abundance of a particular bacterial species, were found in responders to immune checkpoint blockade for melanoma (specifically to anti–programmed cell death protein 1 [PD-1] therapy). A more “bland” composition in which a different species predominated corresponded with a lack of response, in a multi-institutional study presented at the 2017 ASCO–SITC Clinical Immuno-Oncology ­Symposium.¹

Vancheswaran Gopalakrishnan, MPH

“The microbiome can be thought of as the sum of all the microorganisms and their genomes that inhabit the human body. It has been studied across the spectrum of health and disease, especially in cancer,” said study first author Vancheswaran Gopalakrishnan, MPH, of The University of Texas MD Anderson Cancer Center, Houston. “The findings suggest that the microbiome has a significant role in cancer therapy.”

Jennifer A. Wargo, MD, MMSc, the lead investigator on the study and mentor for Mr. Gopalakrishnan, added: “Our findings are early, but if they are validated in larger cohorts across cancer types, they could have significant implications for cancer prognosis and treatment.”

Study Aims

Bacteria in the human body are up to 10 times more plentiful than other types of cells, totaling an estimated 100 trillion microbes of 1,000 different species in the gut alone. The composition of gut bacteria—the microbiota—varies considerably among individuals, possibly influenced by diet and exposure to microbes early in life, the investigators revealed.

We see that patients with unfavorable gut microbiota cannot mount a cytokine response when given checkpoint inhibitors, whereas those with favorable bacteria are able to have a nice induction of proinflammatory cytokines within the periphery.

— Jennifer A. Wargo, MD, MMSc

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To interrogate the relationship between bacteria in the gut and the tumor microenvironment, Dr. Wargo’s team examined baseline and posttreatment tumor samples from patients with metastatic melanoma who either responded, or did not respond, to PD-1–based therapy. They also examined oral samples (from cheek swabs) and fecal samples collected prior to and after treatment, using 16S ribosomal RNA (rRNA) sequencing to distinguish among different bacteria according to their unique genetic ­signatures.

For 221 patients in the study, investigators obtained 233 samples of oral bacteria and 115 fecal samples. Approximately half the patients had received an anti–PD-1 agent, and some had also been treated with ipilimumab (Yervoy) and with targeted therapies.

The researchers hypothesized that individual bacterial “signatures” may differ between groups who responded to PD-1 inhibition and those who did not and that favorable signatures would be associated with an enhanced antitumor immune response (with increased CD8-positive T cells) and enhanced innate immune response. “We thought that insights gained could lead to strategies to enhance responses to therapy through modulation of the microbiome,” Mr. Gopalakrishnan said.

Patterns for Responders vs Nonresponders

Examination of the fecal samples revealed interesting associations with response to anti–PD-1 agents, but oral bacteria failed to demonstrate distinctions. Patients who responded to PD-1 inhibition had significantly greater microbiome diversity in the gut (P = .017) and had increased concentration of the Ruminococcaceae family of bacteria within the Clostridiales order. Patients who did not respond to PD-1 inhibition had a larger population of Bacteroidales, in addition to less microbiome diversity, Mr. ­Gopalakrishnan reported.

Immune-profiling analyses of tumors showed that response to PD-1 inhibition was associated with higher concentrations of immune filtrates in tumors at baseline, including several T-cell markers (CD3, CD8, and PD-1). In particular, higher concentrations of CD8-positive cells in tumors correlated with a higher abundance of Faecalibacteria in the gut, which is part of the ­Ruminococcaceae family.

Whole-genome shotgun sequencing of tumor samples from the “best” and “worst” responders revealed differences in the metabolic pathways that were activated. The initial data suggest that the gut bacteria in responders tend to “turn on” pathways that tip the balance toward biosynthesis, whereas those in nonresponders tend to be more degradative. Dr. Wargo said her “hunch” is this: “An unfavorable gut microbiome is essentially creating chronic inflammation and an immunosuppressive phenotype, which is translating into a weak antitumor immune response.”

Moving Forward

These study findings could have implications for virtually any type of cancer treated with checkpoint inhibitors. The results also suggest that interventions directed at modulating or modifying the microbiome might play a role in cancer treatment strategies, the investigators concluded.

“Meanwhile, we need concerted research efforts to better understand how the microbiome may influence immune responses, as well as an in-depth view on how we can tweak the microbiome so that more patients can benefit from immunotherapy,” Dr. Wargo stated. The “compelling” data notwithstanding, Mr. Gopalakrishnan added, “there is a tremendous amount of work yet to be done.”

One such effort by these researchers is fecal microbiota transplant from human patients into germ-free mice, which could help to characterize the mechanisms through which the gut microbiome may influence systemic and antitumor immunity. Clinical trials are also being designed to test whether modulation of the gut microbiome, for example with probiotics or antibiotics, might enhance the efficacy of immune checkpoint modulators. ■

Disclosure: Mr. Gopalakrishnan reported no potential conflicts of interest. Dr. Wargo reported relationships with GlaxoSmithKline, Genentech, Novartis, Bristol-Myers Squibb, Illumina, and Dava Oncology.

Reference

1. Gopalakrishnan V, Spencer C, Reuben A, et al: Association of diversity and composition of the gut microbiome with differential responses to PD-1 based therapy in patients with metastatic melanoma. 2017 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 02. Presented February 24, 2017.