Cancer inflammation and regulatory T cells

Abstract

Chronic inflammation is essential for cancer growth and metastasis. It follows that factors reducing inflammation would abrogate cancer and restore tissue health. However, roles for anti-inflammatory CD4+ regulatory cells (T(REG)) in cancer are enigmatic and controversial. Our recent data reveal that T(REG) may function in cancer similarly to inflammatory bowel disease or multiple sclerosis, whereby T(REG) accumulate but lack potency to restore tissue homeostasis under inflammatory conditions. Interestingly, early life exposures to diverse environmental organisms reinforce a protective T(REG) phenotype that inhibits cancer. In contrast, hygienic individuals with few exposures earlier in life suffer from a dysregulated T(REG) feedback loop. Consequently, hygienic subjects have increased risk of malignancy later in life. This cancer condition is reversible by blocking underlying inflammation. Taken together, these data help explain increased inflammation-associated cancer rates in hygienic societies and identify targets to abrogate cancer and restore overall health.

Figure 1

Immunological profile is pivotal in cancer risk and outcome. Epidemiologic studies have shown that by midlife multiple preneoplastic lesions exist throughout the human body. However, only a few lesions will become cancerous. Data from mouse models suggest that interactions between infectious agents alter immunological profile and modulate cancer outcomes. Microbial exposures may either inhibit or exacerbate carcinogenesis by triggering immune cell activation or secretion of factors. The “hygiene hypothesis” theorizes that exposures to diverse microbiota reinforce innate immunity and T helper (Th)-1 host responses that lead to balanced and efficient immune responses later in life. By contrast, stringent hygiene conditions deprive the immune system of essential priming rendering T_REG cells ineffectual and readily directed toward a carcinogenic Th-17 host response.

Figure 2

Reciprocal roles of Th-17 and T_REG cells emerge in seemingly diverse diseases: multiple sclerosis (MS), inflammatory bowel disease (IBD) and some types of cancer. Improvements in societal cleanliness have reduced many serious infections but led to an increase in allergies, asthma and autoimmune diseases including multiple sclerosis (MS) and inflammatory bowel disease (IBD). Research using mouse models with experimental allergic encephalitis (EAE), mimicking patients with MS, displays an interleukin (IL)-6-mediated shift in T cells toward pathogenic Th-17. EAE is remedied by downregulation of inflammation and restoration of properly functioning T_REG cells. Some types of inflammation-associated cancers such as colorectal carcinoma (CRC) demonstrate similar immunologic underpinnings. Most surprising were our discoveries that cancers lacking overt inflammation in extraintestinal sites, such as prostate and mammary tissue, display similar T_REG cell distribution and clinical responses after anti-inflammatory therapy. Broader relevancy of these findings is highlighted by observations that non-steroidal anti-inflammatory drugs (NSAIDs) lower the risk of many cancers including nor only CRC but also cancers of prostate, lung and breast in humans. Hygienic rearing increases risk of uncontrollable Th-17 host response.

Figure 3

T_REG cells suppress deleterious immune-mediated pathology and afterward restore epithelial homeostasis. Similarities in roles for T_REG in inflammation and carcinogenesis emerge during bacteriatriggered inflammatory diseases of the gastrointestinal (GI) tract. Gastritis-associated stomach cancer in humans, for example, is caused by infection with Helicobacter pylori, which is classified as a carcinogen by the World Health Organization (WHO). Transgenic mouse models have been widely employed to mimic GI tract inflammation and cancer in humans. Rag2-deficient mice entirely lacking functional lymphocytes are highly susceptible to inflammation-associated carcinoma after infection with closely related bacteria, H. hepaticus. These data from mice indicated that innate immune inflammatory events were sufficient for carcinoma. However, wild-type animals did not develop carcinoma after H. hepaticus infection, showing that effects of lymphocytes were sufficient to protect from cancer. Adoptive transfer of highly purified T_REG cells was sufficient to prevent cancer in Rag−/− mice. Inflammatory bowel disease (IBD) and carcinoma arose only when T_REG failed to suppress inflammation and restore epithelial homeostasis.

Figure 4

Gut microbial infections modulate systemic immune events and outcome of carcinogenesis throughout the body. Helicobacter hepaticus colonizes the large intestine of C57BL/6 Apc^Min\− mice genetically prone to adenomatous intestinal polyps without causing overt typhlocolitis. Nonetheless, malignant transformation of adenomatous polyps is enhanced after infection with H. hepaticus, even in the absence of overt IBD. Surprisingly, H. hepaticus colonization in the lower bowel greatly accelerated carcinogenesis in extraintestinal tissues such as the mammary gland. The tumorigenic effect coincided with a generalized enlargement of the lymph nodes and an elevation of proinflammatory cytokines including TNF-α, interleukin (IL)-6 and IL-17. Interestingly, innate immunity was sufficient for this carcinogenic effect. Mast cells were a feature of intestinal polyps, as well as mammary and prostate carcinogenesis in murine models.

Figure 5

Insufficient microbial exposures earlier in life predispose to uncontrollable inflammatory disorders later in life. Modern sanitization has reduced the incidence of many serious infections. However, individuals living in developed countries with more stringent hygiene practices also suffer from increased incidence of allergies, asthma, autoimmune disorders and some types of inflammation-associated cancer. This is due, at least in part, to dysregulated immune tolerance. Inability of T_REG to inhibit autoimmune diseases such as MS depends on levels of IL-6 that redirect toward a Th-17 host response. Likewise, an IL-10 deficiency during IBD leads to break in immune tolerance and a proinflammatory Th-17 response. Hygienic individuals with a weakened IL-10 and T_REG feedback loop suffer from uncontrollable inflammation that subsequently redirects T_REG cells toward a Th-17-driven procarcinogenic process. In contrast, gut microbial exposures earlier in life may reinforce Th-1 host responses and homeostasis. Taken together, these observations link the immune system, gastrointestinal infections and seemingly divergent downstream phenotypes: IBD, MS and other autoimmune disease and cancer.

Figure 6

Proposed strategies to reinforce protective T_REG functions to abolish cancer and restore overall health. Cancer immunotherapy strategies to date focus primarily on boosting the antitumoral immunological responses of the cancer patient. In that way, T_REG are viewed as an obstacle in tumor immunotherapy and a target for elimination. Recent data suggests that tumor survival and progression are instead vitally dependent on elevated and sustained local and systematic proinflammatory signaling. This raises the possibility that interrupting this proinflammatory loop of signals may be a more direct and constructive route to tumor eradication and restoration of overall health. Thus blocking TNF-α or the STAT3 inflammatory signaling pathway have been shown to rapidly and efficiently abrogate growing cancers in mouse models. Blocking these proinflammatory factors rapidly restores beneficial T_REG functions and epithelial homeostasis. An emerging concept of overall health is systemic benefit of gut microbiota to reinforce beneficial effects of IL-10-dependent anti-inflammatory T_REG cells. Adoptive-transfer studies in mice have shown the unsurpassed ability of gut bacteria-primed T_REG to rapidly restore homeostasis in tissues of the GI tract and also in extraintestinal sites. It was surprising that transfer of T_REG actually suppressed established carcinoma in mice. One therapeutic challenge will be to overcome redirection of T_REG in the proinflammatory tumor environment. Harnessing antineoplastic potential may involve ex vivo cultivation, expansion and stabilization of human T_REG for individualized therapies using autologous transfusions. Broader population-based reinforcement of T_REG could be achieved by dietary habits undertaken earlier in life including probiotics or other bacterialbased modalities, or supplementation with retinoic acid and vitamin D.