As mentioned above, Fcγ receptors of the activating type allow DCs to take up and process antigens and to present antigen derived peptides on MHC class I and class II to CD8+ and CD4+ T lymphocytes, respectively. However, in addition to antigen uptake and processing, the immunologic outcome depends on the state of DC differentiation or maturation. During the steady state, DCs reside in an immature form, and can promote immune tolerance 52
. Exposure to stimuli such as pathogens activates or matures DCs and initiates immunity. The type of immunity depends upon the particular maturation stimulus that the DC encounters. Fcγ receptors not only mediate antigen uptake, but they also influence DC maturation, and the balance between activating versus inhibitory Fcγ receptors is critical to this process () 53
. Conventional DCs express both activating FcγRIIa and FcγRIIIa receptors as well as inhibitory FcγRIIb receptors 54
while the subset of plasmacytoid DCs lacks inhibitory FcγRIIB, expressing only the activating isoform 55
. Thus binding of immune complexes by plasmacytoid DCs in patients with systemic lupus erythematosus reliably activates these cells to produce large amounts of type I interferons, a hallmark of immune activation 56
. The role of plasmacytoid DCs in immune responses following administration of tumor antigen-specific monoclonal antibodies remains to be defined. Initial studies with murine DCs demonstrated that signaling via activating Fc receptors leads to DC maturation 57
and that DCs from mice lacking the inhibitory Fcγ receptors have enhanced capacity for antigen presentation in vitro and in vivo 58
. In addition to the effect on the generation of T cell responses, uptake of antigen via inhibitory Fcγ receptors on DCs can also lead to the generation of B cell responses 59
The recent development of monoclonal antibodies that specifically block the inhibitory FcγRIIB receptor in humans has facilitated the selective manipulation of the balance of Fcγ receptors in human DCs 60,61
. The blockade of the inhibitory Fc receptor on human DCs leads to enhanced dendritic cell maturation 60,61
and, more importantly, augments their ability to generate tumor antigen-specific T cells in vitro 61
. Therefore monoclonal antibodies that preferentially target activating Fcγ receptors may serve a dual role, not only by providing an efficient pathway for the uptake of tumor antigens, but also by delivering a potent maturation stimulus to the antigen presenting DC. Together, these studies suggest that the balance of engagement of activating versus inhibitory Fcγ receptors on human DCs by monoclonal antibodies may be a critical determinant of their ability to boost adaptive immunity.
The recruitment of activating versus inhibitory Fcγ receptors by therapeutic monoclonal antibodies in vivo also depends on host-related features (e.g. Fcγ receptor polymorphisms 24 and cytokine mediated regulation of Fcγ receptors), as well as on the properties of the antibody itself (such as its isotype and glycosylation or sialylation status) 62
. Translation of this biology into improved antibody engineering (e.g. variants with enhanced binding to FcγRIIa or FcγRIIIa), use of bispecific antibodies selectively targeting tumor antigen and activating Fcγ receptors 63,64
or combining current monoclonal antibodies with agents that selectively manipulate signaling via activating and inhibitory Fcγ receptors may lead to improved therapeutic outcome with the next generation of monoclonal antibody trials in patients with malignant disease.