Fc gamma receptors and cancer

Abstract

FcgammaRs are a family of heterogeneous molecules that play opposite roles in immune response and control the effector functions of IgG antibodies. In many cancers, IgG antibodies are produced that recognize cancer cells, form immune complexes and therefore, activate FcgammaR. The therapeutic efficacy of monoclonal IgG antibodies against hematopoietic and epithelial tumors also argue for an important role of IgG antibodies in anti-tumor defenses. Since the 1980s, a series of lines of evidence in experimental models and in humans strongly suggest that FcgammaR are involved in the therapeutic activity of monoclonal IgG antibodies by activating the cytotoxic activity of FcgammaR-positive cells such as NK cells, monocytes, macrophages and neutrophils and by increasing antigen presentation by dendritic cells. Since many cell types co-express activating and inhibitory FcgammaR, the FcgammaR-dependent effector functions of IgG anti-tumor antibodies are counterbalanced by the inhibitory FcgammaRIIB. In addition, some tumor cells express FcgammaR either constitutively, such as B cell lymphomas or ectopically, such as 40% of human metastatic melanoma. The tumor FcgammaR isoform is preferentially FcgammaRIIB, which is functional at least in human metastatic melanoma. This review summarizes these data and discusses how FcgammaRIIB expression may influence the anti-tumor immune reaction and how beneficial or deleterious this expression could be for the efficiency of therapeutics based on monoclonal anti-tumor antibodies.

Immunotherapy of Malignant Disease with Tumor Antigen–Specific Monoclonal Antibodies

“…The latter mechanisms appear to be particularly important for the epidermal growth factor receptor (EGFR)- [16–21], CD20- [22–26] and vascular endothelial growth factor (VEGF)- [27–30] specific mAb. Alternatively, some TA-specific mAb may exert their effects through Fc-based mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) [31,32]. ADCC and CDC are dependent on interactions of antibody Fc domains with cellular Fcγ receptors (FcγR) expressed on immune accessory cells and with the classical complement activating protein C1q, respectively.…”

“…Triggering of both ADCC and CDC not only activates natural killer (NK) cells, neutrophils, mononuclear phagocytes and/or dendritic cells (DC), but also induces secretion of IFN-γ, TNF-α, chemokines and opsonins that recruit immune effector cells. As a result tumor cell proliferation and angiogenesis are inhibited, antigen presentation is increased and tumor cells are lysed [31,32,34]. …”

“…First, transgenic mice that lack type I and type III FcγR have provided the conclusive evidence that mAb are capable of targeting immune effector cells to cancer cells in vivo [31,39]. In this regard, FcγR (−) mice, unlike wild-type mice, fail to demonstrate protective immunity against tumor challenge using a number of antigen/antibody systems.…”

“…Furthermore, the removal of the Fc portion from TA-specific mAb reduces TA-specific mAb related side effects as well as their antitumor activity. In contrast, deletion of the inhibitory type II FcγR (FcγRIIb) results in an increased protective effect suggesting that FcγRIIb modulates TA-specific ADCC activity in vivo [31]. The role of interactions with cellular FcγR in the clinical efficacy of TA-specific mAb-based immunotherapy is further supported by the statistically significant correlation between improved clinical RR to mAb-based immunotherapy and particular “high responder” FcγR polymorphisms in patients with (i) CD20(+) follicular cell lymphoma (FL) treated with rituximab; (ii) metastatic colon cancer (CC) treated with cetuximab, or (iii) metastatic breast cancer (BC) treated with trastuzumab [3].…”

Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles

“…This receptor is expressed on most hematopoietic cells, e.g., monocytes, macrophages, interferon-γ-activated neutrophils, natural killer cells, mast cells and dendritic cells. Complexes of Fc-FcR may induce an antitumor response as summarized by Cassard et al [31]. In some cancers, following IgG recognition of cancer cells, Fcγ receptor (FcγR) on IIC triggers an antitumor response [31].…”