NEWS&ANALYSIS BIOMEDICINE

CREDIT: GLENN MERLINO/CENTER FOR CANCER RESEARCH/NATIONAL CANCER INSTITUTE

Cancer Therapies Use a Little Help From Microbial Friends

www.sciencemag.org

SCIENCE

VOL 342

Published by AAAS

22 NOVEMBER 2013

Downloaded from www.sciencemag.org on January 9, 2014

Outnumbering our own cells more than 10 to tumors in mice chronically treated with anti- Zitvogel, who works at the Institut Gustave one, the microbes thriving peacefully in the biotics and then administered an experimen- Roussy in Villejuif, France, noticed that her human body do more than make up for the tal immunotherapy treatment that included cancer patients undergoing chemotherapy warmth and shelter we provide. They make immune-stimulating DNA fragments and with CTX often developed digestive system us healthy, helping to tune up our immune antibodies. In these mice, whose microbial problems. Looking deeper, she and her colsystems and keep our digestive systems hum- communities had been decimated by the anti- leagues found that CTX disrupted the gut ming. Now, in two papers on pages 967 and biotics, the treatment faltered. It failed to lining. Its tiny projections called villi shrank 971, investigators show that our microbial elicit the typical spike in a tumor-killing pro- and the wall of the small intestine got leaky. guests may also aid in the treatCertain microbes—a few kinds ment of disease. of Gram-positive bacteria— The studies show that in mice, escaped into the rest of body, gut bacteria bolster the effects of the researchers observed. Sevthree antitumor regimens. In each eral, including two Lactobacillus case, when a mouse’s microbial species and Enterococcus hirae, residents are missing, the treattypically settled into the lymph ments are far less effective. “The nodes and spleen. bacteria are demonstrated to be Lab studies showed that this critical,” says Matthew Redinbo, migration may be key to the a structural biologist at the Unidrug’s potency. In a test tube, versity of North Carolina, Chathese so-called Gram-positive pel Hill, who in 2010 showed a bacteria caused immature T cells, bacterial enzyme could limit the such as those found in the spleen toxicity of a cancer drug. “[These and lymph, to turn into Th17 cells, are] insights that further deepen some of which later converted our appreciation of mammalianto memory cells that could promicrobial symbiosis.” long the immune response to the They could ultimately affect tumor. Moreover, feeding such clinical practice, as many cancer bacteria to mice led to an increase patients get antibiotics for infec- Microbe-managed. Gut bacteria prime macrophages (red) in a tumor (purple) in these T cells in the spleen. In tions due to weakened immune to convert to cancer killers during anticancer treatments. contrast, mice bred to be germsystems. “Antibiotic treatments free or treated with a combination may have adverse effects that weren’t pre- tein called tumor necrosis factor, and there of antibiotics or with just vancomycin, which dicted previously,” suggests Lora Hooper, was very little tumor cell death. Likewise, targets Gram-positive bacteria, showed little an immunologist at the University of Texas mice raised in a sterile environment produced to no boost in Th17 cells when given CTX, Southwestern Medical Center in Dallas. much less tumor necrosis factor than nor- and their tumors shrank very little. Investigators are cautious about applying the mal in response to the immunotherapy, and It’s too early to start feeding microbes to mice findings to people, however. The mouse tumors stayed intact. Lacking microbes, the cancer patients, investigators say. “You cannot gut bacteria are not the same as those in our “inflammatory response is severely damp- extrapolate these data to humans without first own intestines, and the details of how the bac- ened,” Trinchieri says. testing in humans,” Trinchieri says. He recomteria collaborate in the destruction of cancer Antibiotics also dampened the response of mends studies of healthy humans to determine cells are still mysterious. macrophages and other immune cells to a dif- how gut microbes affect macrophages and Some cancer treatments work by stimu- ferent regimen, the researchers found. Can- monocytes with and without antibiotic treatlating the immune system to deliver a one- cer drugs such as oxaliplatin work, at least ment. He would also like to know whether two punch. First, cells called macrophages, in part, by damaging tumor cells with mol- there’s any correlation between antibiotic use monocytes, and dendritic cells must be trig- ecules called reactive oxygen species. But and chemotherapy treatment success rates. gered to secrete factors that kill cancer cells. Trinchieri says that in mice taking antibiotNonetheless, the data “illustrate the comVarious cancer drugs have this effect. Next, ics and animals raised to be germ-free, the plex interplay of microbial activity and functhe adaptive immune system kicks in, gener- immune cells made far fewer of the enzymes tion with the immune system and therapies,” ating a more targeted response, as T cells that needed to generate reactive oxygen species. says Jeremy Nicholson, a biochemist at Impespecifically recognize tumor proteins pro- “The gut microbiota have the effect of prim- rial College London. In the future, doctors liferate and keep the immune system rallied ing” the immune system, Trinchieri says. who now tissue-type cancer patients’ tumors against the tumor. Immunologist Laurence Zitvogel found a may also assess their gut bacteria to deterCurious if gut bacteria influenced the out- role for microbes in the response to a third mine the best treatment approach. Zitvogel come of cancer therapies, immunologists treatment, cyclophosphamide (CTX), a drug is already modifying her practice. “We are Giorgio Trinchieri and Romina Goldszmid that combats breast cancers, lymphomas, and going to be very careful about prescribing from the National Cancer Institute in Fred- some brain cancers by increasing the number antibiotics during chemotherapy.” erick, Maryland, and their colleagues grew of a class of immune cells called Th17/Th1. –ELIZABETH PENNISI

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