Abstract
While the immune system has the capacity to recognize and destroy melanoma, tolerance mechanisms often hinder the development of effective anti-tumor immune responses. Since many melanoma antigens are self proteins expressed in normal melanocytes, self antigen exposure before tumor development can negatively impact the function of T cells specific for these self/tumor antigens. However, the contribution of self tolerance to anti-melanoma T cell dysfunction remains largely unexplored. We have previously described a TCR transgenic (Tg) mouse model in which T cells specific for the self/melanoma antigen, tyrosinase-related protein 1 (TRP1), develop in the presence of endogenous TRP1 expression (Ag+) and diminished antigen presentation due to the absence of gamma-interferon-inducible lysosomal thiol reductase (GILT-/-). We show that TRP1-specific T cells from these Ag+GILT-/-Tg mice do not protect from melanoma tumor growth, fail to induce autoimmune vitiligo, and undergo diminished proliferation compared to T cells from Ag-GILT+/+Tg mice. Despite an increased frequency of TRP1-specific Treg cells in Ag+GILT-/-Tg mice compared to Ag-GILT+/+Tg animals, Treg cell depletion only partially rescues the proliferative capacity of T cells from TRP1-expressing mice, suggesting the involvement of additional suppressive mechanisms. An increased percentage of melanoma-specific T cells from Ag+GILT-/-Tg animals express PD-1, an inhibitory receptor associated with the maintenance of T cell exhaustion. Antibody blockade of PD-1 partially improves the ability of TRP1-specific T cells from Ag+GILT-/-Tg mice to produce IL-2. These findings demonstrate that melanoma-specific T cells exposed to a self/melanoma antigen in healthy tissue develop an exhaustion-like phenotype characterized by PD-1-mediated immunosuppression prior to encounter with tumor.
Highlights
The immune system is capable of recognizing melanoma tumors, and patients readily develop melanoma-specific T cell responses [1, 2, 3, 4, 5, 6]
To test the anti-melanoma activity of T cells developing in Ag+gamma-interferoninducible lysosomal thiol reductase (GILT-/-)Tg mice in comparison to Ag-gamma-interferon (IFN)inducible lysosomal thiol reductase (GILT)+/+Tg mice and Ag+GILT+/+Tg mice, animals were subcutaneously injected with B16 melanoma cells and followed for tumor growth
It is possible that diminished presentation of tyrosinase-related protein 1 (TRP1) by antigen presenting cells (APCs) in Ag+GILT-/-Tg mice contributes to the lack of anti-tumor T cell activity in these animals
Summary
The immune system is capable of recognizing melanoma tumors, and patients readily develop melanoma-specific T cell responses [1, 2, 3, 4, 5, 6]. Since many of the known melanoma antigens are self proteins expressed in normal melanocytes, it is important to determine the role of self antigen exposure in melanoma-specific T cell dysfunction. Human studies of tumor-infiltrating lymphocytes specific for self/melanoma antigens are unable to assess the impact of self antigen exposure prior to tumor development on T cell tolerance [14, 15, 16, 17, 18]. It is unclear to what extent self antigen exposure prior to tumor development contributes to the functional impairment of T cells specific for self and melanoma antigens
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