You are the tumor queen, microbiome fiend, IL-17.

The role of IL-17 signaling in cancer remains convoluted due to its role in regulating the gut microbiome. In a recent issue of Cancer Cell, Chandra et al. demonstrate that microbially driven IL-17 signaling promotes tumor growth.

Regulation of tissue-resident memory T cells by the Microbiota.

Resident memory T cells (Trms) predominantly reside within tissue and are critical for providing rapid protection against invasive viruses, fungi and bacteria. Given that tissues are heavily impacted and shaped by the microbiota, it stands to reason that Trms are also influenced by the microbiota that inhabits barrier sites. The influence of the microbiota is largely mediated by microbial production of metabolites which are crucial to the immune response to both viral infection and cancerous tumors. In addition to the effects of metabolites, antigens derived from the microbiota can activate T cell responses. While microbiota-specific T cells may assist in tissue repair, control of infection and anti-tumor immunity, the actual 'memory' potential of these cells remains unclear. Here, we hypothesize that memory responses to antigens from the microbiota must be 'licensed' by inflammatory signals activated by invasion of the host by microorganisms.

Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer.

The composition of the intestinal microbiota is associated with both the development of tumors and the efficacy of anti-tumor immunity. Here, we examined the impact of microbiota-specific T cells in anti-colorectal cancer (CRC) immunity. Introduction of Helicobacter hepaticus (Hhep) in a mouse model of CRC did not alter the microbial landscape but increased tumor infiltration by cytotoxic lymphocytes and inhibited tumor growth. Anti-tumor immunity was independent of CD8+ T cells but dependent upon CD4+ T cells, B cells, and natural killer (NK) cells. Hhep colonization induced Hhep-specific T follicular helper (Tfh) cells, increased the number of colon Tfh cells, and supported the maturation of Hhep+ tumor-adjacent tertiary lymphoid structures. Tfh cells were necessary for Hhep-mediated tumor control and immune infiltration, and adoptive transfer of Hhep-specific CD4+ T cells to Tfh cell-deficient Bcl6fl/flCd4Cre mice restored anti-tumor immunity. Thus, introduction of immunogenic intestinal bacteria can promote Tfh-associated anti-tumor immunity in the colon, suggesting therapeutic approaches for the treatment of CRC.

Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy.

Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.

Regulatory T (Treg) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation and activity of these cells1,2. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME3, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function4-6. At the same time, Treg cells maintain a strong suppression of effector T cells within the TME7,8. As previous studies suggested that Treg cells possess a distinct metabolic profile from effector T cells9-11, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral Treg cells are linked. Here we show that Treg cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of Treg cells in vitro. Treg cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. Treg cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in Treg cells reveals that lactate uptake is dispensable for the function of peripheral Treg cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, Treg cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.

Treg Fragility: A Prerequisite for Effective Antitumor Immunity?

Inhibitory checkpoint blockade has significantly improved patient response rate across numerous tumor types. However, most patients remain unresponsive to immunotherapy, suggesting that unappreciated mechanisms of resistance exist. The tumor microenvironment (TME) is unique and composed of many suppressive cell populations that inhibit antitumor immune responses, including regulatory T cells (Tregs). The TME is nutrient poor, acidic, and hypoxic, creating a challenging microenvironment for immune cells to function and survive. Tregs suppress a wide variety of cell populations through multiple mechanisms and are tasked with limiting tissue damage. Tregs are now considered to be a barrier to effective antitumor immunity. Systemic Treg depletion is not favored because of their critical role in maintaining immune homeostasis and preventing autoimmunity. Reducing Treg function specifically within the TME may provide a more effective, targeted approach to limit the immunosuppressive environment within the tumor without inducing systemic adverse consequences. Targeting molecules that cause Treg instability, characterized by loss of critical Treg transcription factors such as Foxp3, could result in conversion into cells that cause immune pathology, tissue damage, and subsequent autoimmune side effects. Interferon-γ (IFNγ) can cause intratumoral Treg "fragility," which results in loss of suppressive activity and increased IFNγ production without loss of Foxp3 expression and gross Treg "identity." We reviewed the impact Tregs have on the TME and vice versa, and their implications for responsiveness to cancer immunotherapy. We propose that the extent to which intratumoral Tregs develop a "fragile" phenotype following immunotherapy will predict and dictate responsiveness. Cancer Immunol Res; 6(8); 882-7. ©2018 AACR.

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity.

Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1-/-) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1-/- Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.