Recognition of self is emerging as a theme for the immune recognition of human cancer. One question is whether the immune system can actively respond to normal tissue autoantigens expressed by cancer cells. A second but related question is whether immune recognition of tissue autoantigens can actually induce tumor rejection. To address these issues, a mouse model was developed to investigate immune responses to a melanocyte differentiation antigen, tyrosinase-related protein 1 (or gp75), which is the product of the brown locus. In mice, immunization with purified syngeneic gp75 or syngeneic cells expressing gp75 failed to elicit antibody or cytotoxic T-cell responses to gp75, even when different immune adjuvants and cytokines were included. However, immunization with altered sources of gp75 antigen, in the form of either syngeneic gp75 expressed in insect cells or human gp75, elicited autoantibodies to gp75. Immunized mice rejected metastatic melanomas and developed patchy depigmentation in their coats. These studies support a model of tolerance maintained to a melanocyte differentiation antigen where tolerance can be broken by presenting sources of altered antigen (e.g., homologous xenogeneic protein or protein expressed in insect cells). Immune responses induced with these sources of altered antigen reacted with various processed forms of native, syngeneic protein and could induce both tumor rejection and autoimmunity.Most antigens defined on human cancers are expressed both by malignant and normal cells (1-4). Studies of immune recognition of human cancer have shown that differentiation antigens (5), expressed by malignant cells and their normal cell counterparts, comprise a major group of tumor antigens recognized by the host (3). Thus, immunity against cancer in humans might be directed against self molecules. The question then arises how a host might convert from a state of immune tolerance or ignorance to immune response, to differentiation antigens on cancer, and whether such an immune response would be capable of rejecting tumors.The central work in the immune response to human cancer has been done in melanoma. A set of melanoma antigens is expressed both on malignant cells and normal melanocytes or related neuroectodermal cells (6-9). Three of these antigens are melanosomal membrane glycoproteins [tyrosinase͞albino protein, tyrosinase-related protein 1 (or gp75͞brown protein), and the gp100͞pMel 17͞silver protein], and one is an uncharacterized melanocyte-specific protein (MelanA͞MART-1 antigen) (10-23). Thus, one dominant set of antigens recognized on human melanoma are melanocyte differentiation antigens.Products of the brown locus expressed by melanocytes and melanoma are recognized by autoantibodies and T cells of persons with melanoma and are relevant tumor autoantigens (21,23). We have established a syngeneic model in C57BL͞6 mice to investigate immunogenicity of the brown locus protein and potential sequelae of autoimmunity (24). We show that (i) there is apparent tolerance to syngeneic ...
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