Metastatic Melanomas Express Inhibitory Low Affinity Fc Gamma Receptor and Escape Humoral Immunity

Abstract

Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (FcγRIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral FcγRIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the effector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The FcγRIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the FcγRIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral FcγRIIB is fully functional and that its inhibitory potential can be triggered depending on the specificity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy.

A Mouse Monoclonal Antibody against Dengue Virus Type 1 Mochizuki Strain Targeting Envelope Protein Domain II and Displaying Strongly Neutralizing but Not Enhancing Activity

“…K562 cells have only Fc␥RIIa, whereas U937 and HL60 cells express both Fc␥RI and Fc␥RIIa (45,53,54). On the other hand, Fc␥RIIa can bind to mouse IgG1, IgG2a, and IgG2b, but not IgG3, whereas Fc␥RI can bind strongly to mouse IgG2a and IgG3 (55,56). Because no enhancing activity of 7F4 was observed in K562, U937, or HL60 cells, the IgG3 nature of 7F4 is more likely responsible for its "neutralizing activity-only" feature than is the affinity between IgG and Fc␥R.…”

Development and Characterization of Monoclonal Antibodies Specific for Mouse and Human Fcγ Receptors

“…(42,44,46), hFcgRIIB levels have previously been proposed to be important in regulating metastasis (47) (reviewed in Ref. 48), and hFcgRIIA and/or hFcgRIIIA versus hFcgRIIB expression might be important in distinguishing macrophage activation status in vivo, for example, in the tumor setting in which M1/M2 skewing has been proposed.…”

Distinctive properties of metastasis-initiating cells

“…In contrast, BMP4, another member of the TGF-β family, functions as a metastasis suppressor in breast cancer by blocking G-CSF-induced expansion of myeloid-derived suppressor cells (MDSCs) (Cao et al 2014). As another mechanism to compromise the function of innate immune cells during metastasis, melanoma cells express FcγRIIb that negatively regulates B-cell recognition and humoral immunity to promote liver metastasis (Cohen-Solal et al 2010).…”