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Summary: The power of T cells for cancer treatment has been demonstrated by the success of co‐inhibitory receptor blockade and adoptive T‐cell immunotherapies. These treatments are highly successful for certain cancers, but are often personalized, expensive and associated with harmful side effects. Other T‐cell‐modulating drugs may provide additional means of improving immune responses to tumours without these disadvantages. Conventional chemotherapeutic drugs are traditionally used to target cancers directly; however, it is clear that some also have significant immune‐modulating effects that can be harnessed to target tumours. Cyclophosphamide is one such drug; used at lower doses than in mainstream chemotherapy, it can perturb immune homeostasis, tipping the balance towards generation of anti‐tumour T‐cell responses and control of cancer growth. This review discusses its growing reputation as an immune‐modulator whose multiple effects synergize with the microbiota to tip the balance towards tumour immunity offering widespread benefits as a safe, and relatively inexpensive component of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The frequency of CD4+ Foxp3+ regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumour-infiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4+ Foxp3− and CD4+ Foxp3+ T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines ( CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3 CL1), reflected by an enrichment of activated Foxp3− and Foxp3+ T cells expressing T helper type 1-associated chemokine receptors. Notably, we found that CXCR3+ T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3− and Foxp3+ T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3+ cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours. [ABSTRACT FROM AUTHOR]

CD4+Foxp3+ regulatoryT cells (Tregs) have a fundamental role in maintaining immune balance by preventing autoreactivity and immune-mediated pathology. However this role of Tregs extends to suppression of anti-tumor immune responses and remains a major obstacle in the development of anti-cancer vaccines and immunotherapies. This feature of Treg activity is exacerbated by the discovery that Treg frequencies are not only elevated in the blood of cancer patients, but are also significantly enriched within tumors in comparison to other sites. These observations have sparked off the quest to understand the processes through which Tregs become elevated in cancer-bearing hosts and to identify the specific mechanisms leading to their accumulation within the tumor microenvironment. This manuscript reviews the evidence for specific mechanisms of intra-tumoral Treg enrichment and will discuss how this information may be utilized for the purpose of manipulating the balance of tumor-infiltrating T cells in favor of anti-tumor effector cells. [ABSTRACT FROM AUTHOR]

It is clear that CD4 CD25 Foxp3 regulatory T (Treg) cells inhibit chronic inflammatory responses as well as adaptive immune responses. Among the CD4 T-cell population in the skin, at least one-fifth express Foxp3. As the skin is constantly exposed to antigenic challenge and is a common site of vaccination, understanding the role of these skin-resident Treg cells is important. Although the suppressive effect of Treg cells on T cells is well documented, less is known about the types of innate immune cells influenced by Treg cells and whether the Treg cells suppress acute innate immune responses in vivo. To address this we used a mouse melanoma cell line expressing Fas ligand (B16FasL), which induces an inflammatory response following subcutaneous injection of mice. We demonstrate that Treg cells limit this response by inhibiting neutrophil accumulation and survival within hours of tumour cell inoculation. This effect, which was associated with decreased expression of the neutrophil chemoattractants CXCL1 and CXCL2, promoted survival of the inoculated tumour cells. Overall, these data imply that Treg cells in the skin are rapidly mobilized and that this activity serves to limit the amplification of inflammatory responses at this site. [ABSTRACT FROM AUTHOR]

Background: Data from rodent models suggest that a subpopulation of CD4+ T cells, characterized by the constitutive expression of CD25, play a key role in regulating many immune responses. Human CD4+CD25+ T cells also appear to possess a regulatory function, but their role in infections is not fully defined. Objectives: We sought to explore the possibility of a role for CD4+CD25+ T cells in controlling immunity to hepatitis C virus (HCV). We hypothesized that CD4+CD25+ T cells might account for the paucity of immune responses measurable in chronically viremic patients by suppressing the immune responses to HCV antigens. Methods: We compared the responses of PBMCs to 3 different recombinant HCV antigens before and after depletion of CD25+ cells in 15 chronically viremic patients, 14 nonviremic HCV antibody–positive subjects, and 14 healthy control subjects. We also tested the ability of CD4+CD25+ T cells purified from HLA-matched viremic or nonviremic blood to suppress the responses of HCV epitope–specific T-cell clones. Results: To our surprise, depletion of peripheral blood CD25+ cells led to a pronounced increase in proliferation of and IFN-γ production by PBMCs only in nonviremic patients. Furthermore, the CD4+CD25+ T cells purified from HLA-matched nonviremic blood (in contrast to CD4+CD25+ T cells isolated from chronically viremic blood) inhibited the responses of HCV epitope–specific T-cell clones. Conclusion: HCV-specific CD4+CD25+ regulatory T cells appear to accompany successful viral clearance. [Copyright &y& Elsevier]

Recently, a number of studies have documented the presence of high endothelial venules in both mouse and human tumors. The significance of these highly specialized blood vessels within neoplastic lesions, and notably their capacity to influence anticancer immune responses and tumor progression, remains to be fully understood. [ABSTRACT FROM AUTHOR]

Abstract: Tumor-specific T cells must overcome a multitude of suppressive mechanisms to destroy cancerous cells effectively. Furthermore, it appears that the tumor microenvironment facilitates the development of highly immunosuppressive T cells, which may also allow subsequent tumor progression. In colorectal cancer, the relationship between regulatory T cells (e.g. FoxP3+ Tregs) and tumor prognosis and progression is less clear, despite their well-documented ability to impinge on anti-tumor immune responses. Here we explore our current knowledge of colorectal TIL heterogeneity, deciphering subsets which may be of benefit or detriment. [Copyright &y& Elsevier]