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...
The immune system can recognize self antigens expressed by cancer cells. Differentiation antigens are prototypes of these self antigens, being expressed by cancer cells and their normal cell counterparts. The tyrosinase family proteins are well characterized differentiation antigens recognized by antibodies and T cells of patients with melanoma. However, immune tolerance may prevent immunity directed against these antigens. Immunity to the brown locus protein, gp75/ tyrosinase-related protein-1, was investigated in a syngeneic mouse model. C57BL/6 mice, which are tolerant to gp75, generated autoantibodies against gp75 after immunization with DNA encoding human gp75 but not syngeneic mouse gp75. Priming with human gp75 DNA broke tolerance to mouse gp75. Immunity against mouse gp75 provided significant tumor protection. Manifestations of autoimmunity were observed, characterized by coat depigmentation. Rejection of tumor challenge required CD4 ϩ and NK1.1 ϩ cells and Fc receptor ␥ -chain, but depigmentation did not require these components. Thus, immunization with homologous DNA broke tolerance against mouse gp75, possibly by providing help from CD4 ϩ T cells. Mechanisms required for tumor protection were not necessary for autoimmunity, demonstrating that tumor immunity can be uncoupled from autoimmune manifestations. ( J. Clin. Invest. 1998. 102: 1258-1264.)
SummaryIn tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I-associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.
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