Abstract
BackgroundDouble positive (DP) CD4CD8 Tαβ cells have been reported in normal individuals as well as in different pathological conditions including inflammatory diseases, viral infections and cancer, but their function remains to be elucidated. We recently reported the increased frequency of DP Tαβ cells in human breast pleural effusions. This manuscript addresses the question of the existence and above all the role of this non-conventional DP sub-population among tumor associated lymphocytes in melanomas.Methodology/Principal FindingsWe analyzed the intratumoral cell infiltrate in solid metastasis (n = 6) and tumor invaded lymph nodes (n = 26) samples from melanomas patients by multiparametric cytometry. Here we documented for the first time significant increased frequency of DP T cells in about 60% of melanoma tumors compared to blood samples. Interestingly, a high proportion of these cells produced TNF-α in response to autologous melanoma cell lines. Besides, they are characterized by a unique cytokine profile corresponding to higher secretion of IL-13, IL-4 and IL-5 than simple positive T cells. In deep analysis, we derived a representative tumor-reactive DP T cell clone from a melanoma patient's invaded lymph node. This clone was restricted by HLA-A*2402 and recognized both autologous and allogeneic tumor cells of various origins as well as normal cells, suggesting that the target antigen was a ubiquitous self antigen. However, this DP T cell clone failed to kill HLA-A*2402 EBV-transformed B cells, probably due to the constitutive expression of immunoproteasome by these cells.Conclusions/SignificanceIn conclusion, we can postulate that, according to their broad tumor reactivity and to their original cytokine profile, the tumor associated DP T cells could participate in immune responses to tumors in vivo. Therefore, the presence of these cells and their role will be crucial to address in cancer patients, especially in the context of immunotherapies.
Highlights
In the last 20 years, T lymphocytes reactive to antigens expressed by tumor cells have been shown to modulate cancer development in animal models and human cancer patients [1,2]
The current report provides for the first time functional evidence of tumor reactivity of CD4+CD8+ Double positive (DP) Tab cells in human melanomas
We first observed statistically enhanced frequencies of DP T cells compared to metastasis melanomas (P,0.05) and in invaded lymph nodes (P,0.01) than in normal or patients blood
Summary
In the last 20 years, T lymphocytes reactive to antigens expressed by tumor cells have been shown to modulate cancer development in animal models and human cancer patients [1,2]. Recent studies have demonstrated that one of the major mechanisms responsible for the downregulation of T-cell responses against tumors is the presence of several types of suppressor cells within the tumor. We recently reported the increased frequency of DP Tab cells in human breast pleural effusions. This manuscript addresses the question of the existence and above all the role of this non-conventional DP sub-population among tumor associated lymphocytes in melanomas
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