Accumulation of CCR4+ CTLA-4hi FOXP3+CD25hi Regulatory T Cells in Colon Adenocarcinomas Correlate to Reduced Activation of Conventional T Cells

Abstract

BackgroundColorectal cancer usually gives rise to a specific anti-tumor immune response, but for unknown reasons the resulting immunity is not able to clear the tumor. Recruitment of activated effector lymphocytes to the tumor is important for efficient anti-tumor responses, while the presence of regulatory T cells (Treg) down-modulate tumor-specific immunity. We therefore aimed to determine homing mechanisms and activation stage of Treg and effector T cell infiltrating colon tumors compared to cells from the unaffected mucosa in patients suffering from colon adenocarcinoma.Methodology/Principal FindingsLymphocytes were isolated from unaffected and tumor mucosa from patients with colon adenocarcinoma, and flow cytometry, immunohistochemistry, and quantitative PCR was used to investigate the homing mechanisms and activation stage of infiltrating Treg and conventional lymphocytes. We detected significantly higher frequencies of CD25highFOXP3+CD127low putative Treg in tumors than unaffected mucosa, which had a complete demethylation in the FOXP3 promotor. Tumor-associated Treg had a high expression of CTLA-4, and some appeared to be antigen experienced effector/memory cells based on their expression of αEβ7 (CD103). There were also significantly fewer activated T cells and more CTLA-4+ conventional T cells susceptible to immune regulation in the tumor-associated mucosa. In contrast, CD8+granzyme B+ putative cytotoxic cells were efficiently recruited to the tumors. The frequencies of cells expressing α4β7 and the Th1 associated chemokine receptor CXCR3 were significantly decreased among CD4+ T cells in the tumor, while frequencies of CD4+CCR4+ lymphocytes were significantly increased.Conclusions/SignificanceThis study shows that CCR4+CTLA4hi Treg accumulate in colon tumors, while the frequencies of activated conventional Th1 type T cells are decreased. The altered lymphocyte composition in colon tumors will probably diminish the ability of the immune system to effectively attack tumor cells, and reducing the Treg activity is an important challenge for future immunotherapy protocols.

Specific Associations Between Clinical Signs, Immune Cells, Disease Genetic Background and Burden in a Group of Patients with B-Cell Chronic Lymphocytic Leukemia

“…Instead, a significantly higher proportion of CXCR3+ cells within the EM CD4+ T cell subset was found in the majority of patients with LN involvement and a CXCR3+ TFH subset significantly increased in circulation when adenopathies were present. If looking from the Th cytokine profile point of view, our results are in contradiction to data available in the literature suggesting a gradual change in composition of the T cell microenvironment from a Th1 to a Th2 phenotype with the evolution of the disease, in order to secure the selective advantage for tumor growth [27,28]. Based on intracellular cytokines presence, a very recent study found a link between high proportions of circulating Th2 cells in B-CLL patients and the expression of the poor prognostic factor ZAP-70 [29].…”

“…The expression of CXCR3 on the malignant clone was previously reported to be of prognostic value for B-CLL patients [28]. In our study CXCR3 proportion within the B-CLL pool was found to be lower (not significantly, though) in the occurrence of LN/ organ involvement.…”

Human Mucosa-Associated Invariant T Cells Accumulate in Colon Adenocarcinomas but Produce Reduced Amounts of IFN-γ

“…3). This was in contrast to the CD8 + non-MAIT cells, where there was a significant reduction of activated CD69 + cells in the tumor (p , 0.05), as we have previously reported (24). We also analyzed MAIT cell expression of programmed cell death protein 1 (PD-1; CD279), which has been implicated as an attenuating receptor on exhausted T cells, and also on Mycobacterium tuberculosis-reactive MAIT cells (25,26).…”

Ccl22 Diverts T Regulatory Cells and Controls the Growth of Melanoma

“…This leads us to believe that redirecting Treg may be of particular importance to the treatment of micrometastases, whereas larger tumors with greater CCL22 expression may require more drastic treatment. Redirecting Treg might also be useful in other cancers where CCR4 + Treg reportedly interfere with anti-tumor responses, including colon carcinoma, lymphoma and glioblastoma (33, 34, 35). Support for our strategy is most convincing when investigating larger sample numbers, yet our materials were limited.…”