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When the Microbiome Meets Cancer Immunotherapy

Zsiros, Emese MD, PhD, FACOG

doi: 10.1097/01.COT.0000526130.26491.8d
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The human body is a large reservoir of microbial cells, such as bacteria, fungi, and viruses, that live with a symbiotic and commensal community with our body. The human body houses over 100 trillion (10^14) microbes, with over 3.3 million unique microbial genes—which means these microbes outnumber our own body cells by at least 10 times.

Most of these microbes live in the human gastrointestinal tract—particularly in the colon, which provides optimal growth conditions. Firmicutes and Bacteroidetes are the two dominating bacterial divisions in the gut, comprising more than 1,000 bacterial species. The human microbiome plays an essential role in food digestion and nutrient absorption, homeostasis of the epithelial cells lining our gut, and in the proper function of our nervous and immune systems.

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Creation of Microbiome

In early life, the composition and diversity of our microbiome is determined by birth delivery mode—whether we were born by vaginal delivery or C-section—as well as our early childhood feeding (breastfeeding vs. formula feeding), environmental exposures, and hygiene. Breastfeeding helps diversify microbial composition, as sialylated milk oligosaccharides help gut microbiomes colonize and thrive. Cessation of breastfeeding is the major factor leading to gut microbiota maturation; typically, by age 2, a child's microbiome composition resembles that of an adult, dominated by anaerobic Firmicutes and Bacteroidetes.

Early childhood infections and exposure to antibiotics could result in significant loss of microbial richness, which will lead to higher risk for allergies and autoimmune disease later in life. This is concordant with the hygiene hypothesis, in which early-life exposure to specific microbes and parasites is thought to confer protection against allergic and autoimmune disease, highlighting how perinatal environmental influences on the microbiota can determine susceptibility to immune-mediated disease later in life.

Among all the environmental factors, diet has the largest impact on the composition and diversity of gut microbiota. A high-fat diet promotes an increase of Firmicutes and relative reduction of Bacteroidetes, which in turn alters our energy metabolism by promoting more effective caloric intake and, ultimately, weight gain and obesity. Other factors that could severely affect the composition of our microbiome besides diet and obesity include antibiotic use, chemotherapy, radiation, and other lifestyle factors, such as levels of physical activity, circadian rhythm, and sleep.

Most recent research shows that the gut microbiome also modulates human brain function, as some microbiota synthesize neurotransmitters directly (e.g., gamma-aminobutyric acid, or GABA), while many modulate the synthesis of neurotransmitters, such as serotonin, dopamine, norepinephrine, and brain-derived neurotropic factor (Mol Neurobiol 2017;54:4432-4451, J Neurosci 2014;34(46):15490-15496). Microbiotic abnormalities have been linked to reductions in neurotransmitter levels, cognitive deficits, anxiety, depression, chronic pain, and fatigue (J Neurosci 2014;34(46):15490-15496, Adv Appl Microbiol 2015;91:1-62).

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Linking Microbiome & Cancer

Our microbiome also plays an essential role in priming our immune system, developing our innate and adaptive immune cell populations from birth and also maintaining a healthy balance and immune response throughout our entire life (Cell 2014;157(1):121-141). Through the regulation of our immune system, the microbiota plays a complex role in modulating both pro- and anti-tumor immune responses. Disruption of the microbiome leads to changes in intestinal barrier function, which could lead to bacterial translocation and result in chronic inflammation (Mol Neurobiol 2017;54:4432-4451). Chronic inflammation over the years results in altered immune responses and increases risk of tumor formation and progression (Nat Rev Cancer 2013;13(11):800-812).

Increasing evidence suggests that different gut microbiota profiles may be related to the etiology of certain types of cancer, the severity of side effects patients experience, and their response to immunotherapeutic approaches (Nat Rev Cancer 2013;13(11):800-812). Recent preclinical studies in animals have shown that anticancer immunotherapy by the anti-PD-L1 checkpoint inhibitor CTLA-4 relies on the presence of certain gut microbiota (Science 2015;350(6264):1079-1084, Science 2015;350(6264):1084-1089).

Based on what we've seen in animal models of cancer, the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species (B. thetaiotaomicron or B. fragilis); tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade (Science 2015;350(6264):1079-1084). Similarly, another study showed that Bifidobacterium is associated with such antitumor effects, and oral administration of Bifidobacterium alone improved tumor control to the same degree as PD-L1 antibody therapy while combination treatment nearly abolished tumor growth in mice—suggesting that manipulating the microbiota may modulate cancer immunotherapy (Science 2015;350(6264):1084-1089).

Currently, there are many ongoing immunotherapy clinical trials in patients that investigate the role of human microbiome composition in cancer patients, yet there are no tools presently available for identifying those individuals who would benefit most from such treatments. We also have no understanding of how to favorably manipulate our microbiome composition to enhance the efficacy of these new drugs.

At Roswell Park Cancer Institute, Buffalo, N.Y., we are looking to better understand the interactions at work between the microbiome and immune system. We have clinical trials currently underway involving collection of serial human microbiome samples (i.e., stool, skin, and vaginal) from patients with ovarian and endometrial cancers. By analyzing these samples, we hope to be able to correlate microbiome composition with antitumor immune response.

We also have several clinical trials open that investigate the role of certain lifestyle factors—such as physical activity, sleep, level of anxiety, and depression—on the composition of the human microbiome. We look forward to concluding these studies and reporting our results, as we hope that this research will shed light not only on ways the microbiome may alter our immune responses, but also the extent to which we have an opportunity to improve cancer immunotherapy and provide more effective care for our patients by understanding and perhaps manipulating the composition of our microbiomes.

EMESE ZSIROS, MD, PHD, FACOG, is Assistant Professor of Oncology in the Department of Gynecologic Oncology and Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, N.Y.

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