Fc receptors are required in passive and active immunity to melanoma

Abstract

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...

Principles of tumor immunosurveillance and implications for immunotherapy

“…26 In mice, antimelanoma antibodies inhibit tumor growth in a FcgR -dependent manner. 27 In addition, the importance of the Fc -FcgR interaction for antitumor activity was shown for the clinically important antibodies transtuzumab ( Herceptin) and rituximab ( Mabtera, Rituxan ) as well as for intracerebral therapy with an anti -EGF receptor antibody in a brain tumor model. 28,29 The antitumor effect of Herceptin and Rituxan was greatly reduced in mice that lack the activation receptors FcgRI and FcgRIII, whereas disruption of the gene that encodes for the inhibitory receptor FcgRIIB substantially enhanced antitumor activity.…”

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

“…Mice BKO 28 and FcgKO mice 30 were crossed with BALB-neuT mice to generate BALB-neuT/BKO and BALB-neuT/FcgKO mice, respectively. All mice were bred under specific pathogen-free conditions at the Molecular Biotechnology Center (Torino, Italy) and treated in conformity with European Guidelines and policies, as approved by the Ethical Committee of the University of Torino.…”

“…17 IgG2a activate the complement and interact very efficiently with the Fcg receptors on various effector cells. 29 To further elucidate how these passively transferred antibodies induce tumor delay, BALB/c mice KO for the Fc-gamma I/ III receptors (FcgRI/III) (FcgKO mice) 30 were immunized with ECTM or its empty control vector and mated with a BALB-neuT/FcgKO male. FcgKO neu C ECTM female offspring did not display any significant tumor-onset delay over FcgKO neu C control offspring (Fig.…”

Immunothérapie et anticorps monoclonaux

“…Pour abolir l'expression des trois RFc activateurs (I, III, IV), ils ont tiré parti d'une propriété commune à ces récepteurs : tous trois requièrent la présence d'une chaîne associée (chaîne ) pour s'exprimer à la surface des cellules et induire un signal d'activation. Des souris, dont le gène codant la chaîne  a été invalidé, n'expriment donc plus de RFc activateurs ; mais cette absence d'expression n'affecte en rien la génération de lymphocytes T CD8 + spécifiques de l'OVA obtenue dans les souris dont le gène codant la chaîne  avait été invalidé n'étant plus du tout protégées par le traitement par cet Ac [9]. (2) …”