Effective tumor immunity requires recognition of tumor cells coupled with the activation of host effector responses. Fc receptor (FcR) ␥ ؊/؊ mice, which lack the activating Fc␥R types I and III, did not demonstrate protective tumor immunity in models of passive and active immunization against a relevant tumor differentiation antigen, the brown locus protein gp75. In wild-type mice, passive immunization with mAb against gp75 or active immunization against gp75 prevented the development of lung metastases. This protective response was completely abolished in FcR␥-deficient mice. Immune responses were intact in ␥ ؊/؊ mice because IgG titers against gp75 develop normally in ␥ ؊/؊ mice immunized with gp75. However, uncoupling of the Fc␥R effector pathway from antibody recognition of tumor antigens resulted in a loss of protection against tumor challenge. These data demonstrate an unexpected and critical role for FcRs in mediating tumor cytotoxicity in vivo and suggest that enhancement of Fc␥R-mediated antibody-dependent cellular cytotoxicity by inf lammatory cells is a key step in the development of effective tumor immunotherapeutics.Effective immunity against cancer requires the specific recognition and elimination of malignant cells expressing targeted antigens. Antigens recognized on neoplastic cells include viral proteins, products of altered or mutated genes, developmentally reactivated silent gene products, and differentiation antigens expressed by tumor cells and their normal cell counterparts (1, 2). Much of the current effort of vaccine strategies is aimed at eliciting cytolytic T cell responses in which antigen recognition and cytotoxicity are functions shared by a single cell. In antibody-mediated cytotoxicity, however, antigen recognition and cytotoxicity mechanisms are functional properties of distinct cell types.Therapeutic approaches to generate antigen-specific immune responses against tumors have included both passive immunization with mAbs and active immunization using antigens or genes expressing antigens. Passive immunity with antibodies could mediate its cytotoxic effects through complement activation or Fc receptor (FcR) engagement, and immunization with tumor antigens could elicit both cytolytic T cell responses and antibodies capable of triggering effector mechanisms. To clarify the roles of these various pathways in tumor immunity, we have examined the contributions of FcRs to the protective immune response induced against a tumor differentiation antigen by both passive and active immunization in a mouse model of tumor metastases.Three classes of murine FcRs for IgG1, IgG2a, and IgG2b have been characterized-the high-affinity receptor Fc␥RI and the two low affinity receptors Fc␥RII and Fc␥RIII (3). Fc␥RI and III are heterooligomeric receptors, requiring coexpression of the common ␥ chain for their assembly and signaling functions. Cross-linking these receptors results in cell activation. Fc␥RII, in contrast, is a single chain inhibitory receptor, aborting activation through ITAM (immu...

SummaryThe immune system can recognize differentiation antigens that are selectively expressed on malignant cells and their normal cell counterparts. However, it is uncertain whether immunity to differentiation antigens can effectively lead to tumor rejection. The mouse brown locus protein, gp75 or tyrosinase-related protein 1, is a melanocyte differentiation antigen expressed by melanomas and normal melanocytes. The gp75 antigen is recognized by autoantibodies and autoreactive T cells in persons with melanoma. To model autoimmunity against a melanocyte differentiation antigen, mouse antibodies against gp75 were passively transferred into tumorbearing mice. Passive immunization with a mouse monoclonal antibody against gp75 induced protection and rejection of both subcutaneous tumors and lung metastases in syngeneic C57BL/6 mice, including established tumors. Passive immunity produced coat color alterations but only in regenerating hairs. This system provides a model for autoimmune vitiligo and shows that immune responses to melanocyte differentiation antigens can influence mouse coat color. Immune recognition of a melanocyte differentiation antigen can reject tumors, providing a basis for targeting tissue autoantigens expressed on cancer.

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 ...