Lymphocyte-melanoma interaction: role of surface molecules.
The coexistence of tumor-specific immunity with a progressing tumor is observed in most experimental systems and remains one of the major paradoxes of tumor immunology. Expression of several surface molecules on melanoma cells, e.g., intercellular adhesion molecule 1 (ICAM-1) or major histocompatibility complex (MHC) class II, has been associated with an aggressive tumor growth and an reduced host antitumor response. HLA class I expression is also frequently altered in melanoma compared to melanocytes. Given the central role of these molecules in the restriction of T cell recognition, regulation of tumor HLA class I expression might also be a strategy for the evasion of immune surveillance by the malignant cells. The fact that it is now possible to clone antigen-specific T cells from tumor patients, as well as the relevant autologous tumor cell lines, enabled us to establish a model system to investigate possible tumor escape mechanisms from immunosurveillance. Using this system, we were able to demonstrate that purified soluble ICAM-1 or 12-fold-concentrated cell-free melanoma supernatants, containing shed ICAM-1, were able to inhibit conjugate formation between T cell clones and the autologous melanoma cells as efficiently as monoclonal antibodies against CD11a, Soluble ICAM-1 also abrogated the MHC-restricted killing of the melanoma by T cell clones. We further observed that a number of CD4+ T cell clones and melanoma cell lines established from the same tumors form conjugates with each other, leading to an increase of [Ca2+]i in the T cell clone; however, this interaction failed to induce interleukin-2 production or proliferation of the T cell clone. Furthermore, this interaction rendered the T cell clone unresponsive to subsequent stimulation. All these effects were MHC class II restricted. Therefore, the melanoma was capable of delivering antigen-specific signals to the T cell clone, but did not deliver the costimulatory signals, e.g., a B7/CD28 interaction, necessary for full T cell activation. Transfection of the melanoma with an expression vector containing a B7 cDNA with subsequent B7 expression on its cell surface renders the melanoma a fully competent antigen-presenting cell which is able to induce a nuclear factor binding to the interleukin-2 promoter in the specific T cell clone, followed by enhanced interleukin-2 transcription, synthesis, and T cell proliferation.
Becker
J C
JC
Department of Dermatology, University of Würzburg, Germany.
Bröcker
E B
EB
D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000502:physiology*; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D006680:HLA Antigens; D009363:Neoplasm Proteins; D018799:Intercellular Adhesion Molecule-1