Fc receptor inside‐out signaling and possible impact on antibody therapy

Abstract

Fc receptors (FcR) are expressed on immune cells and bind to the Fc tail of antibodies. This interaction is essential for FcR-mediated signaling and triggering of cellular effector functions. FcR activation is tightly regulated to prevent immune responses by non-antigen bound antibodies or in the absence of 'danger signals'. FcR activity may be modulated at the plasma membrane via cross-talk with integrins. In addition, cytokines at the site of infection/inflammation can increase FcR avidity, a process referred to as inside-out signaling. This regulatory mechanism has been described for FcγRI (CD64), FcγRIIa (CD32a), and FcαRI (CD89) and is also well-known for integrins. Key cellular events during inside-out signaling are (de)phosphorylation, clustering, cytoskeleton rearrangements, and conformational changes. The latter can be studied with antibodies that specifically recognize epitopes exposed by the active (high affinity) or inactive (low affinity) state of the FcR. These antibodies are important tools to investigate the role of FcR activation in disease settings. Research on FcR has gained momentum with the rise of monoclonal antibodies (mAb) entering the clinic for the treatment of cancer and other diseases. The clinical outcome of mAb therapy may be improved by increasing FcR avidity by cytokine stimulation.

Validation of Neutrophil CD64 Blood Biomarkers to Detect Mucosal Inflammation in Pediatric Crohn’s Disease

“…CD64 and the other activating Fcγ receptors have been found to increase inside-out signaling (avidity) where ligand binding capacity to Fcγ receptors increases with no change in CD64 cell surface expression. 32 …”

Immunoglobulin A: magic bullet or Trojan horse?

“…Ligand binding is regulated via a mechanism referred to as inside-out signalling [25]. During this process, cytokines prime cells to increase binding capacity of FcaRI, while receptor expression levels are not modulated [26].…”

“…Furthermore, only FcaRI targeting leads to the release of proinflammatory cytokines, further highlighting the advantage of using IgA over IgG [52]. By priming neutrophils with GM-CSF and G-CSF via inside-out signalling, the efficacy of antibody therapy might be further enhanced [26,44]. In vivo studies on IgA antitumour therapy are limited, partially because mice do not express FcaRI.…”

Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth

“…The contribution of ADCC to antibody efficacy in patients is also supported by studies demonstrating associations between therapeutic efficacy and the expression of certain Fcγ receptor allotypes [11]. FcγR activation can be stimulatory or inhibitory to effector cells, depending on which receptor is triggered and which cells are activated [12]. With respect to cancer immunotherapy, NK cells are central in that they express only the activating FcγRIIIa receptor (CD16) and no inhibitory antibody receptors underscoring a major role in promoting tumor cell killing [13].…”