Gut-Centric Hypothesis: Prior Exposures to Microbes Explain Beneficial Roles of TREG
Stimulated by a gut-centric systemic homeostasis hypothesis, we set out to explore and explain the paradoxical roles of TREG in cancer using several different mouse models of cancer and adoptive cell transfer methodologies. It was found that TREG may suppress, promote, or have no effect in carcinogenesis depending upon their timing and prior exposure to gut bacterial antigens and presence of IL-10. Under some conditions, adoptive transfer of TREG rapidly led to apoptosis of emerging tumor cells. Using as a model organism an opportunistic pathogen,Helicobacter hepaticus, commonly residing in the lower bowel of mice, we have shown in Rag2-deficient mice (otherwise lacking lymphocytes) that gut microbiota modulate inflammatory bowel disease and inflammation-associated colon cancer, a cancer process inhibited by properly functioning IL-10-dependent TREG. Subsequently, by introducing H. hepaticus into the large bowel flora of mice lacking the APC tumor suppressor gene (ApcMin/+), we found that intestinal polypogenesis was greatly enhanced by bacteria and subsequently suppressed by immune-competent TREG. Furthermore, adenomas of infected ApcMin/+ mice progressed into adenocarcinoma, a transition atypical of polyps of aged-matched uninfected controls. Interestingly, ApcMin/+mice having H. hepaticus in their gut flora were prone to develop cancer in tissues distant from intestine, such as prostate and the mammary glands. H. hepaticus-induced tumorigenic events were inhibited by supplementation with TREG from immune-competent wild type donor mice.
A potent treatment to counteract these local and systemic H. hepaticus-induced tumorigenic events was supplementation with TREG in an IL-10-dependent manner. Purified TREG exhibited greatest anti-cancer potency when taken from donor mice previously colonized withH. hepaticus. By contrast, TREG taken from donor mice without prior H. hepaticus exposure were ineffective, and in some cases actually enhanced tumorigenesis. Based on these results, we theorize that the tumor microenvironment is subject to systemic inflammatory events arising from environmental exposures in the gastrointestinal tract (Figure 1). This microbe-inducible pro-inflammatory condition contributes to tumor trophic signaling. Interestingly, bacterial antigen triggered IL-10-dependent activities in the GI-tract impart sustained protection from the aforementioned events, resulting in immune cell recruitment, including TREG, which, by being more potent in their anti-inflammatory roles, work locally and systemically to suppress sepsis, myeloid precursor mobilization, and inflammatory signaling important in extra-intestinal cancer evolution. These systemic events comprise the tumor macroenvironment.
Front. Immunol., 07 April 2014 | doi: 10.3389/fimmu.2014.00157