RESUMO
Neutrophil-mediated tumor cell lysis is more efficiently triggered by FcalphaRI (CD89), than by FcgammaRI (CD64). This difference is most evident in immature neutrophils in which FcgammaRI-mediated tumor cell lysis is absent. In this study, we show that FcR gamma-chain-dependent functions (such as Ab-dependent cellular cytotoxicity and respiratory burst), as well as signaling (calcium mobilization and MAPK phosphorylation), were potently triggered via FcalphaRI, but not via FcgammaRI, in immature neutrophils. Internalization, an FcR gamma-chain-independent function, was, however, effectively initiated via both receptors. These data suggest an impaired functional association between FcgammaRI and the FcR gamma-chain, which prompted us to perform coimmunoprecipitation experiments. As a weaker association was observed between FcgammaRI and FcR gamma-chain, compared with FcalphaRI and FcR gamma-chain, our data support that differences between FcalphaRI- and FcgammaRI-mediated functions are attributable to dissimilarities in association with the FcR gamma-chain.
Assuntos
Antígenos CD/metabolismo , Neutrófilos/imunologia , Receptores Fc/metabolismo , Receptores de IgG/metabolismo , Animais , Medula Óssea/imunologia , Linhagem Celular Tumoral , Humanos , Imunoprecipitação , Camundongos , Explosão Respiratória , Transdução de SinaisRESUMO
Antitumor Abs are promising therapeutics for cancer. Currently, most Ab-based therapies focus on IgG Ab, which interact with IgG FcR (FcgammaR) on effector cells. In this study, we examined human and mouse neutrophil-mediated tumor cell lysis via targeting the IgA FcR, FcalphaRI (CD89), in more detail. FcalphaRI was the most effective FcR in triggering tumor cell killing, and initiated enhanced migration of neutrophils into tumor colonies. Importantly, immature neutrophils that are mobilized from the bone marrow upon G-CSF treatment efficiently triggered tumor cell lysis via FcalphaRI, but proved incapable of initiating tumor cell killing via FcgammaR. This may provide a rationale for the disappointing results observed in some earlier clinical trials in which patients were treated with G-CSF and antitumor Ab-targeting FcgammaR.
