Cancer Immunology at the Crossroads: Microbiology Microbiota Modulation of Myeloid Cells in Cancer Therapy

Myeloid cells represent amajor component of the tumormicroenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy. Cancer Immunol Res; 3(2); 103–9. 2015 AACR. The Microbiota Modulates Inflammation and Immunity by Priming Myeloid-Cell Differentiation and Functions Commensalmicroorganisms are abundant on all our epithelial barrier surfaces, where, directly or through released molecules, they interact with innate receptors and cytoplasmic sensors, thus regulating the development, tone, and maintenance of local inflammation and immunity (1). The interplay between the host immune system and the microbiota prevents tissue-damaging inflammatory responses to the commensals and controls the growth of indigenous pathobionts while it sets the stage for immune responses against pathogenic infections (2–4). This homeostatic immune regulation may be disrupted by changes in the microbial community that alter the symbiotic relationship with the microbiota, and the resultant microbial imbalance is commonly referred to as dysbiosis (5). Many regulatory mechanisms involved in these local interactions have been elucidated (6). In addition to local immunity, the commensal microbiota regulates systemic inflammation, innate resistance, and adaptive immunity, affecting both resistance to infection and autoimmunity (7–12). Maturation of the immune system is dependent on exposure to the microbiota following birth (13). In germ-free (GF) mice, which are protected from exposure to external microbes, spleens and peripheral lymph nodes are hypoplastic, mesenteric lymph nodes are mostly missing, whereas primary immune organs, thymus and bone marrow, have normal appearance (7). However, GF mice mount normal or heightened responses to nominal purified antigens but defective responses to pathogens due to deficient innate and antigen-presenting cell functions (7, 8, 14). Unlike barrier immunity, which can be modulated in a compartmentalized manner by the local microbiota (15), the abundant gut microbiota has been considered primarily responsible for the control of immune homeostasis at the systemic level; however, contributions of microbiota from other anatomic locations (e.g., oral cavity) need to be reevaluated (16). Themechanismbywhich themicrobiota regulates immunity at distant sterile anatomic sites remains largely unknown. Tight junctions among epithelial cells as well as mechanisms mediated by soluble factors (e.g., antibacterial peptides, antibodies) and innate or adaptive immune cells render the skin/mucosal barrier relatively impermeable to microbes and their products (17). However, some bacterial translocation takes place even under normal physiologic conditions. In addition, increased barrier permeability may be induced by infections, inflammation, and immunodeficient states that alter antimicrobial defense mechanisms and epithelial integrity (18–21). Dysbiosis directly affects immunity and also, by changing the predominance of bacterial species with different effects on host immunoregulation, alters the composition of other colonizing microorganisms. For example, overgrowth of the commensal fungal Candida species is often observed following antibioticsinduced gut dysbiosis, and it has been shown to result in increased prostaglandin E2 plasma concentration and M2-macrophage polarization in the lung, leading to heightened allergic airways inflammation (22). Recent studies on the modulation of immunity against infection by microbiota have provided insight into how commensals regulate systemic immunity. GF or antibiotics-treated mice have defective myelopoiesis and impaired neutrophil homeostasis with an increased susceptibility to late-onset sepsis (23).Defective myelopoiesis also makes GF mice unable to resist acute infection with Listeria monocytogenes; however, they have an enhanced adaptive immune response to vaccination with an attenuated L. monocytogenes strain, a result compatible with normal or heightened adaptive response to nominal antigens in GF mice (14, 24, 25). Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Leidos BiomedicalResearch, Inc., Bethesda,Maryland. InstitutNational de laSant eet de la Recherche M edicale, Institut Gustave Roussy, Villejuif, France. Universit e Paris-Sud, Kremlin Bicêtre, France. Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. Corresponding Authors: Giorgio Trinchieri, National Cancer Institute, NIH, Building 37, Room 4146, Bethesda, MD 20892. Phone: 301-496-1648; Fax: 301 846-1673; E-mail: [email protected]; and R.S. Goldszmid, [email protected] doi: 10.1158/2326-6066.CIR-14-0225 2015 American Association for Cancer Research. Cancer Immunology Research www.aacrjournals.org 103 on May 28, 2017. © 2015 American Association for Cancer Research. cancerimmunolres.aacrjournals.org Downloaded from