Sunday, November 8, 2015

Gut Microbiome Composition Influences Effectiveness of Immunotherapy in Mice

M. Vétizou et al., “Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota,” Science Express, doi:10.1126/aad1329, 2015. 

A. Sivan et al., “Commensal Bifidobacterium promotes antitumor immunity and facilitates anti–PD-L1 efficacy,” Science Express, doi:0.1126/science.aac4255, 2015. 

The Scientist:
The presence of certain types of gut microbes in mice can boost the anti-tumor effects of cancer immunotherapy, according to two studies from independent research teams published today (November 5) in Science Express.

Cancer immunotherapies that block immune inhibitory pathways are now available as treatments for several tumor types, yet patients’ responses to these therapies vary. Aside from the presence of T cells within the tumor before the start of treatment, it has not been clear what other factors are linked to a response to these antibodies. The two studies published today, while not the first to suggest that gut microbes can influence the efficacy of cancer therapy, provide a definitive link between gut microbiome composition and cancer immunotherapy response and implicate the positive role of specific bacterial species.

“These interesting papers combine two of the hottest areas in science—the microbiome and immunology—showing that gut bacteria can activate [host] anti-tumor responses,” said Timothy Hand of the department of immunology at the University of Pittsburgh who was not involved in either study.

“These are beautiful studies that give mechanistic views of how the gut microbiota is critical for regulating the immune system in the context of an immune checkpoint blockade to encourage the immune system in fighting cancer,” agreed Justin Sonnenburg, a microbiome researcher at the Stanford School of Medicine who was also not involved in the research. “The microbiota is connected to our biology in both direct and indirect ways, and these works are adding to the list of how the microbiota is incredibly important for our health.”

Thomas F. Gajewski, a cancer clinician and researcher at the University of Chicago, and his colleagues were interested to understand what leads some cancer patients to have a strong immune response against a tumor—in the form of T cells that infiltrate the tumor. “Differences in immune responses to cancer may be due to genetic variants, differences in the tumor mutations, environmental differences, or a combination of these factors,” explained Gajewski.

To explore the role of the gut microbiome, the researchers studied two groups of the same strain of laboratory mice that had been bred at two different mouse facilities and were known to harbor different commensal bacteria in their GI tracts. When both sets of mice were implanted with melanoma tumors, tumors grew less aggressively in the mice sourced from the Jackson Laboratory (JAX) and these mice had more robust T-cells responses against the tumors. When both mouse groups were housed together, the differences in tumor responses disappeared, leading the researchers to hypothesize that commensal microbes from the JAX mice had colonized the other mouse population, sourced from Taconic Biosciences. Sure enough, a fecal transplant from the JAX mice to the other group resulted in better anti-tumor T-cell responses and slower tumor growth in the Taconic Biosciences group, even when housed separately.

Next, the researchers decided to test the effects of an anti-PD-L1 immunotherapy antibody. The therapy slowed tumor growth to a greater extent in the JAX compared to the Taconic Biosciences mice. Taconic Biosciences mice treated with the antibody had similar tumor control and immune responses to mice who’d received a fecal transplant from the JAX animals, but combining the immunotherapy and the fecal transplant led to greater tumor control.

Sequencing the gut microbiome of the mice, the researchers found that Bifidobacterium species were linked to the anti-tumor immune response and that adding a cocktail of these microbes to the Taconic Biosciences mice with melanoma resulted in the same benefit as the fecal transplant. The team also found that the dendritic cells isolated from either the JAX mice or Bifidobacterium-treated Taconic Biosciences mice are able to better stimulate tumor-specific T cells in vitro.

“These effects of the gut microbiome on the anti-tumor immune response were stronger than we had anticipated,” said Gajewski.

In the second study, led by immunologist Laurence Zitvogel of INSERM in France, researchers found that the effect of treating mice harboring sarcomas, melanoma, or colorectal tumors with another immunotherapy antibody, against CTLA-4, depended on the presence of Bacteroides species; germ-free or antibiotics-treated mice did not enjoy tumor control as a result of the therapy. Adding Bacteroides species to the germ-free and antibiotics treated mice restored the immunotherapy’s anti-tumor benefit. Interestingly, adding murine memory T cells targeting the gut microbes to the mice had the same effect, suggesting that it is the immune system’s response to commensal microbes that readies it to fight tumors.

Analyzing gut microbiome of 25 metastatic melanoma patients, the INSERM researchers also found that some patients had Bacterioides as part of their gut microbiomes and that a fecal transplant from these patients into germ free mice also restored the anti-CTLA-4 therapy’s anti-tumor effects.

“What was quite exciting for us is that using microbes may be a way to improve the efficacy of immunotherapies without increasing their toxic side effects,” said study author Mathias Chamaillard, an immunologist at the Center of Infection and Immunity at the University of Lille in France. Both groups of researchers are now sorting out the details of how the gut microbes stimulate the immune system to act against tumors.

Of course, whether the gut microbial species identified in these mouse studies will have the same effect in people is not clear. “The impact of the gut microbiota is probably different depending on the context,” said Gajewski. “We’re starting to understand that that one type of bacteria is not going to cure everything.”

N. Iida et al., “Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment,” Science, 342:967-70, 2013.

S. Viaud et al., “The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide,” Science, 342:971-76, 2013.

Gut microbes—or a lack thereof—can significantly affect the efficacy of certain cancer therapies elsewhere in the body, according to two studies appearing in Science today (November 21). Independent teams show in mouse models of cancer that gut microbes appear to modulate the host immune responses sparked by the anticancer drug cyclophosphamide, as well as by certain types of immunotherapy and chemotherapy. Both found that germ-free mice responded less well to tumor-targeting therapies than animals with rich gut microbiomes.

“Most of the time we think about the gut microbiome shaping the local environment. Now these papers are breaking the glass ceiling and going into extra-intestinal organs . . . and influencing activities of drugs,” said Christian Jobin, a professor of infectious diseases and pathology at the University of Florida who reviewed both studies, and was not involved in either. “That’s really quite unique.”

While previous studies have unearthed similar “evidence that the inflammatory response to microbes is useful to cancer treatment,” noted New York University School of Medicine microbiologist Martin Blaser, who was not involved in the research, the new studies represent an “important” extension of that work. It’s becoming increasingly clear, he said, that “the gut microbiome has adjuvant functions in terms of inflammation and immunity,” he said.

“Both studies are very exciting in that they show initial links between gut microbiota and [response to] therapies,” agreed Harvard University’s Peter Turnbaugh, who was not involved in the investigations. The papers, he added, “underscore the importance [of] microbes in shaping not just our initial predisposition to disease, but also our recovery from it.”

Studying tumor-bearing mouse models, scientists at France’s INSERM found that the drug cyclophosphamide altered the animals’ gut microbiota composition and triggered the translocation of certain Gram-positive bacteria species to secondary lymphoid organs. Once there, these bacteria prompted the generation of specific immune cells, called “pathogenic” T helper 17 (pTH17) cells, as well as memory TH1 immune responses, which aided cyclophosphamide efficacy. In germ-free mice and animals administered antibiotics to extinguish Gram-positive bacteria, their tumors were resistant to cyclophosphamide.

“We found out that the translocation of these bacteria and immunization of the host against these bacteria . . . is why we see so many TH1 cells in the spleen or in the blood of patients [treated with cyclophosphamide],” said Laurence Zitvogel, the INSERM immunologist who led the study. More broadly, she and her colleagues propose that gut microbes may often modulate the immune response to anticancer therapies.

The National Cancer Institute’s Romina Goldszmid and her colleagues have suggested a similar hypothesis—that gut microbes shape inflammation within the tumor microenvironment. The researchers found that the mouse gut microbiome shaped both local and systemic inflammation, which is known to contribute to the development of cancer. In germ-free or antibiotics-treated mice, Goldszmid and her colleagues found that tumor-infiltrating myeloid-derived cells responded poorly to CpG-oligonucleotide immunotherapy and platinum chemotherapy, in part because of reduced cytokine production and lower production of reactive oxygen species, respectively.

“I was a bit surprised that the gut bacteria could have such an impact on modulating distant inflammation of the tumor environment,” said Goldszmid. Though she and her colleagues suspected that the CpG therapy’s antitumor effect was rooted in a proinflammatory response already known to be regulated by gut microbiota, the team was not expecting “the extent [to] which inflammatory cells’ reactive oxygen species production was required for the genotoxic effect of the [platinum] drugs, and strictly dependent on the presence of gut microbiota,” study coauthor Giorgio Trinchieri, who heads up the Cancer Immunobiology Section at NCI’s Center for Cancer Research, elaborated in an e-mail.

Goldszmid, Trinchieri, and Zitvogel all cautioned that extensive validation work remains to be done, and that their findings have yet to be confirmed in humans. Further studies are also needed to unravel the mechanisms by which gut microbes influence inflammation and immunity.

Taken together, the INSERM- and NCI-led studies stress the potential importance of the gut microbiome during cancer treatment. Much like researchers are identifying genomic variants that correlate with drug response, “by looking at the microbiome, maybe some people don’t have the bugs to show the best response to drugs,” said Jobin. “If we learned more about how these bacteria impact drug efficacy, then we could be more precise in the way we intervene on disease activity.”

Both studies also point to the perils of antibiotic overuse.

“It has been demonstrated, and our present study has confirmed, that after antibiotic treatment the bacterial composition in the gut never returns to its initial composition,” Trinchieri said. “Thus, our findings raise the possibility that the frequent use of antibiotics during a patient’s lifetime—or to treat infections related to cancer and its side effects—may affect the success of anticancer therapy.”

And microbial resistance to antibiotics is on the rise. “On the microbial side, it would be interesting to know whether resistance to these compounds plays a role in determining whether or not [gut bacteria] could continue to provide these immunomodulatory effects,” Turnbaugh added.

Blaser echoed this sentiment. “We can harness our microbes to help us fight cancer,” he said. “Conversely, when we disrupt our microbes, it might make fighting cancer harder.”

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