Subject(s)
Biomarkers, Tumor/metabolism , Melanoma/metabolism , Melanoma/secondary , Skin Neoplasms/metabolism , Chemokines/metabolism , Gene Expression Regulation, Neoplastic , Humans , Lymphatic Metastasis , Matrix Metalloproteinases/metabolism , Neoplasm Metastasis/diagnosis , Predictive Value of Tests , Receptors, Chemokine/metabolism , Skin Neoplasms/pathologyABSTRACT
Innate and adaptive immunity have not evolved separately. In this regard, the NKG2D molecule first identified on NK cells and classified as an activating NK cell receptor is also an important receptor for CD8(+) T cells. Functional analyses of human NKG2D and its ligands, i.e. UL16 binding proteins (ULBP) and MHC class I chain-related (MIC), have so far focused on immune cell-target cell situations because of the expression of NKG2D ligands on infected, stressed or transformed cells. Here, however, we address a possible function of NKG2D/ULBP-1 during the initiation of T cell responses. ULBP-1 can be detected on mature dendritic cells both in situ in the T cell areas of lymph nodes as well as in vitro after artificial maturation. FCM analysis further demonstrated that although NKG2D is expressed to some degree on all analyzed T cell subsets from peripheral blood, in vitro stimulation of T cells results in up-regulation of NKG2D on proliferating T cells. Using the sentinel lymph nodes of primary melanoma as a model for induction of defined T cell responses in vivo, we were able to demonstrate the expression of NKG2D on melanoma-associated antigen-specific T cells. Thus, our results suggest a role for NGK2D-ULBP-1 in the induction or reactivation of T cell responses.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Carrier Proteins/biosynthesis , Dendritic Cells/immunology , Histocompatibility Antigens Class I/biosynthesis , Lymphocyte Activation/immunology , T-Lymphocyte Subsets/immunology , Carrier Proteins/immunology , Dendritic Cells/metabolism , Flow Cytometry , GPI-Linked Proteins , Histocompatibility Antigens Class I/immunology , Humans , Immunohistochemistry , Intracellular Signaling Peptides and Proteins , Lymph Nodes/cytology , Lymph Nodes/immunology , Melanoma/immunology , Membrane Proteins , NK Cell Lectin-Like Receptor Subfamily K , Polymerase Chain Reaction , Receptors, Immunologic/immunology , Receptors, Immunologic/metabolism , Receptors, Natural Killer Cell , Sentinel Lymph Node BiopsyABSTRACT
Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin(96-104) epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.
