The regulation of the proximal step in the immune response, antigen presentation by dendritic cells, determines the immunological outcome of encounter with antigen: tolerance vs. activation of the cellular and/or humoral response. Dendritic cells express several receptors for the Fc portion of immunoglobulin G (FCgammaR), which facilitate this process by internalization of antigen-IgG complexes (immune complexes, ICs), induction of dendritic cell maturation, and enhancement of major histocompatibility complex (MHC) class I- and class II-restricted antigen presentation. Thus FcgammaR mediated antigen presentation accomplishes a long-sought goal in tumor-vaccine design, combined activation of both CD4 and CD8 T cell pathways. In experiments demonstrating the importance of the FcgammaR antigen presentation pathway in vivo, our preliminary data indicate that dendritic cells loaded with antibody-opsonized tumor cells or Ova-containing ICs induce T cell activation in vivo and rejection of Ova-bearing tumors in mice. Furthermore, tumor prevention is accompanied by the induction of both class II and class I restricted CD4 and CD8 T cell responses. FcgammaR-mediated trapping and endocytosis of immune complexes has been known to efficiently induce class II restricted antibody responses, however, this is the first demonstration in vivo of an endocytically acquired antigen, in this case immune complex uptake, resulting in """"""""cross-priming"""""""" or the induction of a class I restricted cellular immune response. This link of ICs and class I responses suggests that antibody produced during an initial exposure to antigen during an ongoing immune response may provide the host further protection by initiation of a subsequent T cell-mediated cellular response, and suggests novel approaches to tumor vaccine development.
Our specific aims are to: 1) Determine the mechanism of tumor protection and specifically whether activating and inhibitory FcgammaRs coordinately regulate CD8 and Th1 -polarized CD4 responses. 2) Establish the potency and general applicability of IC-loaded dendritic cell vaccination approaches to HER2 transgenic models of breast cancer. 3) Determine whether FcgammaR uptake enhances class I antigen presentation in human systems and specifically whether antibody-mediated T cell priming occurs in Trastuzumab-treated patients.
