Fcγ receptors: genetic variation, function, and disease

Abstract

Fcγ receptors (FcγRs) are key immune receptors responsible for the effective control of both humoral and innate immunity and are central to maintaining the balance between generating appropriate responses to infection and preventing autoimmunity. When this balance is lost, pathology results in increased susceptibility to cancer, autoimmunity, and infection. In contrast, optimal FcγR engagement facilitates effective disease resolution and response to monoclonal antibody immunotherapy. The underlying genetics of the FcγR gene family are a central component of this careful balance. Complex in humans and generated through ancestral duplication events, here we review the evolution of the gene family in mammals, the potential importance of copy number, and functionally relevant single nucleotide polymorphisms, as well as discussing current approaches and limitations when exploring genetic variation in this region.

Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors

“…Genetics Distinct germline polymorphisms in immune cell receptors have the potential to place limits on immunotherapies. Given consistent associations between certain FcgRIII receptor polymorphisms and the outcome of rituximab (anti-CD20) treatment in rheumatoid arthritis, FcgRIII polymorphism has been suggested to influence the efficacy of rituximab in follicular lymphoma, although data to the contrary signify that this remains to be confirmed (Hargreaves et al, 2015). Differences in antibody-dependent cell-mediated cytotoxicity (ADCC) by natural killer (NK) cells or monocytes due to certain FcgRIII polymorphisms have also been associated with the outcome of trastuzumab treatment in HER2-positive breast cancer (Musolino et al, 2008) and similarly in cetuximab treatment of head and neck squamous cell carcinoma cell lines (Ló pez-Albaitero et al, 2009).…”

FcγR requirements leading to successful immunotherapy

“…Although studies in mice have provided overwhelming and convincing data showing that FcγR are critical for almost all therapeutic mAb (reviewed in ), data providing evidence for the FcγR dependence of anti‐cancer mAb in humans have, to date, been more challenging, reliant on genetic associations with clinical outcome and in vitro assays, neither of which are definitive. The bases of the genetic studies have been polymorphic differences between individuals that affect either the affinity, signaling capacity, or expression of FcγR . As these differences are naturally occurring variants of differing frequency and strength of function (rather than designed knockouts as employed in mice), it is perhaps not surprising that many clinical association studies disagree about the predictive capacity of FcγR polymorphic differences and mAb responses.…”

Understanding the Genomic Structure of Copy-Number Variation of the Low-Affinity Fcγ Receptor Region Allows Confirmation of the Association ofFCGR3BDeletion with Rheumatoid Arthritis

“…IgG binding can either activate or inhibit downstream cellular responses depending on the particular ITAM or ITIM containing Fcγ receptor that is engaged. Dysregulation of Fcγ receptors is important in a number of different inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Kawasaki disease [Niederer et al., ; McKinney and Merriman, ; Hargreaves et al., ]. Furthermore, not only are Fcγ receptors critical for disease etiology but also for successful immunotherapy of patients with hematological and solid cancers by mediating the effector functions of therapeutic monoclonal antibodies [Dahal et al., ].…”