The role of regulatory T cells (Tregs) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating Tregs can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, Tregs have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different Treg subsets. We report the preferential expansion of a Treg subset in human CC with potent T cell–suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from Tregs present in healthy donors by their coexpression of Foxp3 and RORγt. Tregs with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the RORγt gene in Foxp3+ cells in polyp-prone mice stabilized Treg anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor–α in polyp-prone mice reduced polyp number but not to the same extent as loss of RORγt. Surprisingly, loss of IL-17A had a dual effect: IL-17A–deficient mice had fewer polyps but continued to have RORγt+ Tregs and developed invasive cancer. Thus, we conclude that RORγt has a central role in determining the balance between protective and pathogenic Tregs in CC and that Treg subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient.

T-regulatory (Treg) cells play a major role in cancer by suppressing protective antitumor immune responses.

Purpose of review Tumor growth elicits antigen-specific cytotoxic as well as immune suppressive responses. Interleukin-10 (IL-10) is a key immune-suppressive cytokine produced by regulatory T-cells (Tregs) and by helper T-cells (TH). Here we review pleiotropic functions of IL-10 that impact the immune pathology of cancer. Recent findings The role of IL-10 in cancer has become less certain with knowledge of its immune stimulatory functions. IL-10 is needed for T-helper cell functions, T-cell immune surveillance, and suppression of cancer-associated inflammation. By promoting tumor specific immune surveillance and hindering pathogenic inflammation IL-10 is emerging as a key cytokine in the battle of the host against cancer. Summary IL-10 functions at the cross roads of immune stimulation and immune suppression in cancer. Immunological mechanisms of action of IL-10 can be ultimately exploited to develop novel and effective cancer therapies.

Interleukin-10 (IL-10) is elevated in cancer and is thought to contribute to immune tolerance and tumor growth. Defying these expectations, the adoptive transfer of IL-10 expressing T-cells to mice with polyposis attenuates microbial-induced inflammation and suppresses polyposis. To gain better insights into how IL-10 impacts polyposis, we genetically ablated IL-10 in T-cells in APCΔ468 mice and compared the effects of treatment with broad-spectrum antibiotics. We found that T-cells and Tregs were a major cellular source of IL-10 in both the healthy and polyp-bearing colon. Notably, T-cell-specific ablation of IL-10 produced pathologies that were identical to mice with a systemic deficiency in IL-10, in both cases increasing the numbers and growth of colon polyps. Eosinophils were found to densely infiltrate colon polyps, which were enriched similarly for microbiota associated previously with colon cancer. In mice receiving broad-spectrum antibiotics, we observed reductions in microbiota, inflammation, and polyposis. Together our findings establish that colon polyposis is driven by high densities of microbes that accumulate within polyps and trigger local inflammatory responses. Inflammation, local microbe densities, and polyp growth are suppressed by IL-10 derived specifically from T-cells and Tregs.

T-regulatory cells (Treg) and mast cells (MC) are abundant in colorectal cancer (CRC) tumors. Interaction between the two is known to promote immune suppression or loss of Treg functions and autoimmunity. Here, we demonstrate that in both human CRC and murine polyposis the outcome of this interaction is the generation of potently immune suppressive but proinflammatory Treg (ΔTreg). These Treg shut down IL10, gain potential to express IL17, and switch from suppressing to promoting MC expansion and degranulation. This change is also brought about by direct coculture of MC and Treg, or culture of Treg in medium containing IL6 and IL2. IL6 deficiency in the bone marrow of mice susceptible to polyposis eliminated IL17 production by the polyp infiltrating Treg, but did not significantly affect the growth of polyps or the generation of proinflammatory Treg. IL6-deficient MC could generate proinflammatory Treg. Thus, MC induce Treg to switch function and escalate inflammation in CRC without losing T-cell–suppressive properties. IL6 and IL17 are not needed in this process.

An imbalance of commensal bacteria and their gene products underlies mucosal and, in particular, gastrointestinal inflammation and a predisposition to cancer. Lactobacillus species have received considerable attention as examples of beneficial microbiota. We have reported previously that deletion of the phosphoglycerol transferase gene that is responsible for lipoteichoic acid (LTA) biosynthesis in Lactobacillus acidophilus (NCK2025) rendered this bacterium able to significantly protect mice against induced colitis when delivered orally. Here we report that oral treatment with LTA-deficient NCK2025 normalizes innate and adaptive pathogenic immune responses and causes regression of established colonic polyps. This study reveals the proinflammatory role of LTA and the ability of LTA-deficient L. acidophilus to regulate inflammation and protect against colonic polyposis in a unique mouse model. dendritic cells | regulatory T cells | anti-inflammatory I dentifying bacterial gene products that enhance protective versus pathogenic inflammation in the gut is critical to rebalance homeostasis in gastrointestinal (GI) chronic inflammatory diseases and malignancies. Commensal Lactobacillus species (i.e., Lactobacillus acidophilus) are normal inhabitants of the natural microbiota in the human GI tract (1, 2). L. acidophilus stimulates innate cells to produce inflammatory and regulatory cytokines through interaction of their surface layer proteins and other cell surface components (3-7). To investigate the potential role of lipoteichoic acid (LTA) of L. acidophilus in the induction of inflammatory signals, we deleted the phosphoglycerol transferase gene (LBA0447) that synthesizes LTA. LTA is a zwitterionic glycolipid found in the cell wall of several Gram-positive bacterial strains, including L. acidophilus, which stimulates dendritic cells (DCs) through Toll-like receptor 2, resulting in cytokine release (8, 9). Disruption of LTA synthesis generated a L. acidophilus derivative (NCK2025) that mitigates colitis in mice (10). Based on these observations and those of others (11,12), it was proposed that LTA induces inflammation and that its absence significantly attenuates overt intestinal inflammation.Inflammation has a tumor-promoting role in mice with polyposis and in human colon cancer (13)(14)(15)(16)(17). T regulatory cells (Tregs) critically regulate inflammation and play a protective role in polyposis (15, 18) and colon cancer (19-21). However, chronic interaction of Tregs with proinflammatory cells and their cytokines can reverse the anti-inflammatory properties of these cells and render them proinflammatory (15,16,22,23). Consensus suggests that interactions between lymphocytes and myeloid cells regulate pro-vs. antitumor immunity (17, 24), and we hypothesized that the gut microbiota plays an essential role in control of this balance. We used L. acidophilus NCK2025, deficient in LTA, to investigate the moderation of pathogenic inflammation within the tumor microenvironment in a unique mouse model of colonic polyposis...

Cholesterol is known to modulate the physical properties of cell membranes but its direct involvement in cellular signaling has not been thoroughly investigated. Here we show that cholesterol specifically binds many PDZ domains found in scaffold proteins, including the N-terminal PDZ domain of NHERF1/EBP50. This modular domain has a cholesterol-binding site topologically distinct from its canonical protein-binding site and serves as a dual specificity domain that bridges the membrane and juxta-membrane signaling complexes. Disruption of the cholesterol binding activity of NHERF1 largely abrogates its dynamic colocalization with and activation of cystic fibrosis transmembrane conductance regulator, one of its binding partners in the plasma membrane of mammalian cells. At least seven more PDZ domains from other scaffold proteins also bind cholesterol and have cholesterol-binding sites, suggesting that cholesterol modulates cell signaling through direct interactions with these scaffold proteins. This mechanism may provide an alternative explanation for the formation of signaling platforms in cholesterol-rich membrane domains.