New research into gut bacteria may shed light on the mystery of responsiveness to immunotherapy. The multi-institutional study, presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, showed that patients with metastatic melanoma who responded to anti–PD-1 agents had increased diversity of intestinal microbiome. Nonresponders, on the other hand, corresponded with less diversity as well as a different composition of gut bacteria.
The multi-institutional study, presented at the 2017 ASCO-SITC Clinical Immuno-Oncology Symposium, showed that patients with metastatic melanoma who responded to anti–PD-1 agents had increased diversity of intestinal microbiome. Nonresponders, on the other hand, corresponded with less diversity as well as a different composition of gut bacteria.
According to the researchers, these results have “far-reaching implications” for cancer prognosis and treatment and suggest that modulation of the gut microbiome may be used to enhance immune response.
“The microbiome can be thought of as the sum of all the microorganisms and their genomes that inhabit the human body,” said lead study investigator Vancheswaran Gopalakrishnan, BDS, MPH, of The University of Texas MD Anderson Cancer Center, Houston. “It has been studied across the spectrum of health and disease, and especially in cancer. The findings suggest that the microbiome has a significant role in cancer therapy.”
Jennifer A. Wargo, MD, in whose laboratory Dr Gopalakrishnan is a doctoral candidate, noted in background information related to their study that bacteria in the human body outnumber other types of cells by as much as 10 to 1. In addition, wrote Dr Wargo, an estimated 100 trillion bacteria, representing more than 1000 different species, reside in the human gut alone. The composition of gut bacteria varies dramatically from one person to another, and this variation is thought to be influenced by diet and exposure to microbes early in life.
To test the relationship between the gut microbiome and the tumor microenvironment, Dr Wargo’s team examined baseline and posttreatment tumor samples from patients with metastatic melanoma who either did or did not respond to PD-1–based therapy. Investigators obtained a total of 233 samples of oral bacteria and 115 fecal samples from 221 patients in the study. Approximately half of the patients (n = 110) had been treated with an anti–PD-1 agent. Some patients had also received the anti–CTLA-4 antibody ipilimumab and/or targeted therapies, the authors noted.
Dr Wargo and colleagues used a ribosomal RNA probe to characterize the diversity and composition of bacteria present in the oral and fecal samples. Immune profiling was also performed in available tumors at baseline (via a 7-marker immunohistochemistry panel of CD3, CD8, PD-1, PD-L1, granzyme B, RORγT, and FoxP3).
Fecal Bacteria Reveal Patterns of Response
Although comparison of oral bacteria showed no clear bacterial “signatures” that distinguished responders from nonresponders to PD-1 inhibition, analysis of fecal bacteria yielded more promising results. As Dr Gopalakrishnan reported, the 30 patients who responded to PD-1 inhibition had significantly greater microbiome diversity (P = .017). More specifically, patients who responded to treatment had an increased concentration of the Ruminococcaceae family of bacteria within the Clostridiales order. Patients who did not respond to PD-1 inhibition, however, had a larger population of Bacteroidales, in addition to less diversity of gut bacteria.
In baseline tumor samples of responders, immune profiling also demonstrated significantly higher concentrations of immune infiltrates, with a positive correlation between CD8, CD3, PD-1, and FoxP3 T-cell density, and an abundance of Faecalibacteria in the gut.
When the 5 best responders were compared with the 5 worst responders, whole genome sequencing of tumor samples also revealed differences in metabolic pathways that were activated. Although still early in the research, said Dr Gopalakrishnan, these data indicate that gut bacteria in responders may “turn on” pathways that lead toward biosynthesis.
As for the mechanism of action, Dr Wargo hypothesized that an unfavorable gut microbiome is creating chronic inflammation and an immunosuppressive phenotype, which is translating into the tumor.
“There are also differences in innate immune cells in the tumor microenvironment,” Dr Wargo explained. “In the cytokine profiles, 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.”
Regardless of the underlying cause, however, these initial data have left the investigators optimistic concerning future treatment strategies.
“These findings have implications that extend beyond melanoma to other types of cancers that have been treated with immunotherapeutic agents, such as PD-1/PD-L1 inhibitors,” Dr Gopalakrishnan observed. “The results also suggest that interventions directed at modulating or modifying the microbiome might have a role in cancer treatment strategies.”
“Our findings are early, but if they are validated in larger cohorts across cancer types, they may have significant implications for cancer prognosis and treatment,” Dr Wargo added. “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.”