Melanomas can develop at several different anatomical sites including the eye and skin. Although skin and eye melanomas share a common cellular origin, the pathobiology of ocular melanomas is unique and distinct from skin tumors. Ocular melanomas are distinguished by their: histological appearance, pattern of tumor growth, expression of melanoma-associated-antigens, and metastatic spread. Moreover, ocular tumors in mice induce a deviant cell-mediated immune response. Despite these uncommon characteristics, relatively little information is known about the T cell mediated immune response to human choroidal melanomas. In this grant application we propose to: (a) determine if human choroidal melanomas are immunogenic by characterizing the cytotoxic T cell and T helper cell responses, and (b) identify the defect in the immune response which prevents cytotoxic T cells from eliminating the tumor. We hypothesize that choroidal melanomas induce a deviant tumor-specific T cell response in which precursor cytotoxic T cells are clonally expanded, but fail to differentiate into cytolytic T cells capable of eliminating tumor cells. The failure to initiate precursor cell differentiation results from an inability of T helper cells to secrete the necessary lymphokines. The implications of this hypothesis are that ocular melanomas induce, an immune response with the potential to eliminate the tumor, if full T helper activity is restored, and cytotoxic T cells are present.
The specific aims of this grant will address the following questions: (1) are precursor cytotoxic T cells present among peripheral blood lymphocytes (PBL) and tumor-infiltrating-lymphocytes (TIL), (2) are cytotoxic T cells present among TIL capable of lysing ocular melanoma cells in situ, and (3) are T helper cells present among PBL and TIL; what lymphokines are secreted when these cells are restimulated in vitro with tumor antigens.
