CD4+CD25+FOXP3+ Regulatory T Cells Suppress Anti-Tumor Immune Responses in Patients with Colorectal Cancer

Abstract

BackgroundA wealth of evidence obtained using mouse models indicates that CD4+CD25+FOXP3+ regulatory T cells (Treg) maintain peripheral tolerance to self-antigens and also inhibit anti-tumor immune responses. To date there is limited information about CD4+ T cell responses in patients with colorectal cancer (CRC). We set out to measure T cell responses to a tumor-associated antigen and examine whether Treg impinge on those anti-tumor immune responses in CRC patients.Methodology and Principal FindingsTreg were identified and characterized as CD4+CD25+FOXP3+ using flow cytometry. An increased frequency of Treg was demonstrated in both peripheral blood and mesenteric lymph nodes of patients with colorectal cancer (CRC) compared with either healthy controls or patients with inflammatory bowel disease (IBD). Depletion of Treg from peripheral blood mononuclear cells (PBMC) of CRC patients unmasked CD4+ T cell responses, as observed by IFNγ release, to the tumor associated antigen 5T4, whereas no effect was observed in a healthy age-matched control group.Conclusions/SignificanceCollectively, these data demonstrate that Treg capable of inhibiting tumor associated antigen-specific immune responses are enriched in patients with CRC. These results support a rationale for manipulating Treg to enhance cancer immunotherapy.

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…IL-10, IL-8, TGF-β), prostaglandins, and VEGF, which redirect immune responses toward a favorable environment for growth [12,14,32]. Additionally, regulatory T cells (Treg) contribute to an immunosuppressive microenvironment through a cyclooxygenase-2-prostaglandin-2-dependent mechanism, direct cell-cell contact, or by the release of cytokines, like TGF-β, thereby facilitating tumor growth (see further below) [1,33,34]. Furthermore, TAMs, especially from the M2 phenotype, also release factors that favor growth and metastasis (as described above).…”

Tumor-Released Survivin Induces a Type-2 T Cell Response and Decreases Cytotoxic T Cell Function, in Vitro

“…Pro-inflammatory Th17 cells produce IL-17 to recruit neutrophils and induce the production of pro-inflammatory factors in immune cells [7,8]. In contrast to their Th17 counterpart, Treg cells suppress inflammatory responses and regulate the function of other T cell populations [3,[9][10][11]. Characterized as CD4 + CD25 + CD127 low Foxp3 + , Tregs are important in preventing over-activation of the immune system as well as responses to autoantigens [10,12].…”

“…This shift is correlated to poor disease progression, as the anti-tumor response is inhibited and a pro-tumor environment is created [13,14,24]. Additionally, Treg cells have been implicated in promoting tumor growth by suppressing activation of tumor-specific cytotoxic T cells due to their expression of auto antigens [11,[25][26][27]. As with type 2 T cells, increased numbers of Tregs within the tumor correlates with poor prognosis and decreased responsiveness to immunotherapies [25][26][27].…”

High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability

“…Treg cells represent a heterogeneous group of T cells that are defined on the basis of their ability to control the activation and function of antigen-reactive T cells in the periphery, thereby preventing self-reactivity (reviewed in Knutson et al, 2007). Treg cells can suppress reactivity of tumour antigen-specific T cells in CRC patients (Clarke et al, 2006). The number of Treg cells in the peripheral blood and the tumour itself are increased in patients suffering from gastrointestinal malignancies including CRCs (Ichihara et al, 2003;Sasada et al, 2003;Kono et al, 2006;Loddenkemper et al, 2006;Ling et al, 2007).…”