Abstract
Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibody-coated tumor cells. Here we describe an approach to potentiate tumor immunity whereby hapten-specific polyclonal antibodies are recruited to tumors by coating tumor cells with the hapten. Vaccination of mice against dinitrophenol (DNP) followed by systemic administration of DNP targeted to tumors by conjugation to a VEGF or osteopontin aptamer elicits potent FcR dependent, T cell mediated, antitumor immunity. Recruitment of αGal-specific antibodies, the most abundant naturally occurring antibodies in human serum, inhibits tumor growth in mice treated with a VEGF aptamer–αGal hapten conjugate, and recruits antibodies from human serum to human tumor biopsies of distinct origin. Thus, treatment with αGal hapten conjugated to broad-spectrum tumor targeting ligands could enhance the susceptibility of a broad range of tumors to immune elimination.
Highlights
Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibodycoated tumor cells
The ability of dendritic cells (DC) to take up tumor antigens is a pivotal step in the induction of antitumor immunity, underscored by studies showing that antibody blockade of CD47, an inhibitory “don’t-eat-me” receptor upregulated on many tumor cells, potentiates the induction of protective antitumor T cell immunity in mice[1,2]
FcR-mediated functions have an important role in the mechanism of action of therapeutic monoclonal antibodies targeting CD20 (Rituximab), Her[2] (Trastuzumab), and EGFR (Cetuximab)[5], and the marked effects of antibodies targeting CTLA-4 or PD-L1 may be mediated via Fc–FcR depletion of intratumoral Treg[6,7,8] and F4/80+ myeloid cells[9], respectively
Summary
Uptake of tumor antigens by tumor-infiltrating dendritic cells is limiting step in the induction of tumor immunity, which can be mediated through Fc receptor (FcR) triggering by antibodycoated tumor cells. Low and colleagues have shown that recruiting antifluorescein (FITC) polyclonal antibody to folate receptor expressing tumor cells in mice by coating tumor cells in situ with systemically administered folate-targeted FITC inhibited tumor growth in a T cell-dependent manner[21]. It is tempting to speculate that the polyclonal nature of the miMHC-specific antibodies capable of engaging multiple FcRs of complementary mode of action, and thereby providing the synergy discussed above, contributed to the remarkable antitumor effects seen in this study. The antibody-coated tumor cells will in turn attract Fc receptor expressing phagocytic and dendritic cells, resulting in ADCC-, ADCP-, complement-dependent lysis or uptake and processing for antigen presentation, respectively
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