Abstract
Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.
Highlights
Through the production of recombinant GA733, an epithelial cell adhesion molecule (EpCAM), Fc fusion protein, and an anti-GA733 monoclonal therapeutic antibodies (mAbs), anti-GA733 IgG immune complex (IC) were obtained. These were subsequently administered to immunocompetent mice, leading to the induction of a Th2 response followed by the generation of anti-GA733 mouse antibodies
Some studies suggest that dendritic cells (DCs)-targeted vaccination strategies employing hapten:tumor Ags, or hapten:whole-tumor cell preparations combined with the use of antihapten immunization to boost the DC response led to vaccination success [103,104]
These experiments further showed that consensus domain III sequence (cEDIII)-polymeric immunoglobulin G scaffolds (PIGS) engaged FcγRI, FcγRIIA, and FcγRIIIA, which is expected for IgG1-Fc derived molecules [60,68]
Summary
Cancer remains one of the biggest burdens on healthcare systems worldwide. It is the second major cause of death after cardiovascular disorders. Effective tumor immune control is hampered by the occurrence of “exhausted”, nonfunctional T cells in tumors [3] Based on these observations, cancer immunotherapy has emerged as a treatment option to harness components of the patient’s IS to fight tumor cells. CDC1 DCs are thought to possess an intrinsic cross-presentation capability They can effectively activate CD8+ T cells, as well as promote CD4+ T-helper type 1 (Th1) cells (3), while cDC2 DCs can be induced to cross-present Ags (see below). They contribute to CD8+ T-cell activation [9]. PDCs have been studied in the context of antigen presentation, where they were described to induce antigen cross-presentation post-activation [10,11,12,13,14,15]
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