In the Section of Cancer Immmunobiology as well as in a few other Sections within the Cancer and Inflammation Program as well as other part of CCR there is great need to understand the role of the gut flora in the pathogenesis of inflammatory and immune colitis and in mouse models of colitis-associated cancer. We extensively use mice deficient for immune or inflammation-related genes and it is always difficult to distinguish a direct effect of those genes on the colitis or cancer, or an indirect one through the regulation of the intestinal flora. Other collaborative studies in the program are directed to the study of the role of the liver immune response in controlling liver carcinogenesis and it is likely that the inflammatory-immunological microenvironment in the liver is also significantly affected by the composition of the intestinal flora. Overall these studies would greatly benefit by the access to a germ free facility and particularly by the availability of committed expertise in gut microbiology based on state of the art sequencing and bioinformatics, expertise that it is of difficult access to single laboratories but that could be efficiently provided to a multidisciplinary extended consortium of laboratories with overlapping interests in this field. We have established methods for the determination of mouse microbioma using 454 sequencing of 16 RNA, cytofluorimetric analysis of FISH labeling of specific bacterial types, and possibly other approaches including microarray. Sequencing and bioinformatic expertise will be needed. We also initiated studies with germ free mice, gnotobiotic mice with defined intestinal flora, and mice reconstitute after antibiotic treatment. Initially we plan to study the role of the intestinal flora in experimental models of colitis and colitis-associated cancer using mice genetically deficient for inflammation-controlling genes such as MyD88, IL-18, TNF, TLRs, and others. The role of commensal microbiota in energetic alteration associated with cancer (i.e. obesiti, cachxia, anorexia) is being planned in murine experimental models and in observational clinical experimentation. Compartmentalized control of skin immunity by resident commensals (Science. 2012;337:1115-9). Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment (submitted for publication). The gut microbiome influences both local and systemic inflammation. Although the role of inflammation in cancer is well documented, whether commensal bacteria can exert distant effects on the inflammation in the sterile tumor microenvironment remains unclear. Here we show that microbiota perturbation impairs the response of subcutaneous cancers to CpG-oligonucleotide-immunotherapy or platinum chemotherapy. In antibiotic-treated or germ-free mice, decreased cytokine production from tumor-infiltrating monocyte-derived cells following CpG-ODN treatment reduced tumor necrosis, whereas deficient chemotherapy-induced production of reactive oxygen species by myeloid cells impaired genotoxicity and tumor destruction. Thus, optimal response to cancer immunotherapy and chemotherapy requires an intact commensal microbiota that acts distantly by modulating myeloid-derived cell function in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment.

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National Cancer Institute (NCI)
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Trinchieri, Giorgio (2018) Natural Killer Cells Detect a Tumor-Produced Growth Factor: A Vestige of Antiviral Resistance? Trends Immunol 39:357-358
Linehan, Jonathan L; Harrison, Oliver J; Han, Seong-Ji et al. (2018) Non-classical Immunity Controls Microbiota Impact on Skin Immunity and Tissue Repair. Cell 172:784-796.e18
Sui, Yongjun; Dzutsev, Amiran; Venzon, David et al. (2018) Influence of gut microbiome on mucosal immune activation and SHIV viral transmission in naive macaques. Mucosal Immunol 11:1219-1229
Vetizou, Marie; Trinchieri, Giorgio (2018) Anti-PD1 in the wonder-gut-land. Cell Res 28:263-264
Dutzan, Nicolas; Abusleme, Loreto; Bridgeman, Hayley et al. (2017) On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Immunity 46:133-147
Dzutsev, Amiran; Badger, Jonathan H; Perez-Chanona, Ernesto et al. (2017) Microbes and Cancer. Annu Rev Immunol 35:199-228
Stroncek, David F; Butterfield, Lisa H; Cannarile, Michael A et al. (2017) Systematic evaluation of immune regulation and modulation. J Immunother Cancer 5:21
Rosshart, Stephan P; Vassallo, Brian G; Angeletti, Davide et al. (2017) Wild Mouse Gut Microbiota Promotes Host Fitness and Improves Disease Resistance. Cell 171:1015-1028.e13
Roy, Soumen; Trinchieri, Giorgio (2017) Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer 17:271-285
Namasivayam, Sivaranjani; Maiga, Mamoudou; Yuan, Wuxing et al. (2017) Longitudinal profiling reveals a persistent intestinal dysbiosis triggered by conventional anti-tuberculosis therapy. Microbiome 5:71

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