Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
Ridgeview Instruments AB, Vänge, Sweden.
Front Immunol. 2019 Apr 11;10:704. doi: 10.3389/fimmu.2019.00704. eCollection 2019.
Antibody therapy of cancer is increasingly used in the clinic and has improved patient's life expectancy. Except for immune checkpoint inhibition, the mode of action of many antibodies is to recognize overexpressed or specific tumor antigens and initiate either direct F(ab')-mediated tumor cell killing, or Fc-mediated effects such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/P) after binding to activating Fc receptors. All antibodies used in the clinic are of the IgG isotype. The IgA isotype can, however, also elicit powerful anti-tumor responses through engagement of the activating Fc receptor for monomeric IgA (FcαRI). In addition to monocytes, macrophages and eosinophils as FcαRI expressing immune cells, neutrophils are especially vigorous in eliminating IgA opsonized tumor cells. However, with IgG as single agent it appears almost impossible to activate neutrophils efficiently, as we have visualized by live cell imaging of tumor cell killing. In this study, we investigated Fc receptor expression, binding and signaling to clarify why triggering of neutrophils by IgA is more efficient than by IgG. FcαRI expression on neutrophils is ~2 times and ~20 times lower than that of Fcγ receptors FcγRIIa and FcγRIIIb, but still, binding of neutrophils to IgA- or IgG-coated surfaces was similar. In addition, our data suggest that IgA-mediated binding of neutrophils is more stable compared to IgG. IgA engagement of neutrophils elicited stronger Fc receptor signaling than IgG as indicated by measuring the p-ERK signaling molecule. We propose that the higher stoichiometry of IgA to the FcαR/FcRγ-chain complex, activating four ITAMs (Immunoreceptor Tyrosine-based Activating Motifs) compared to a single ITAM for FcγRIIa, combined with a possible decoy role of the highly expressed FcγRIIIb, explains why IgA is much better than IgG at triggering tumor cell killing by neutrophils. We anticipate that harnessing the vast population of neutrophils by the use of IgA monoclonal antibodies can be a valuable addition to the growing arsenal of antibody-based therapeutics for cancer treatment.
癌症的抗体疗法在临床上的应用越来越广泛，提高了患者的预期寿命。除了免疫检查点抑制，许多抗体的作用模式是识别过表达或特定的肿瘤抗原，并在与激活的 Fc 受体结合后启动直接 F(ab')介导的肿瘤细胞杀伤，或 Fc 介导的效应，如补体依赖性细胞毒性 (CDC)和抗体依赖性细胞介导的细胞毒性/吞噬作用 (ADCC/P)。临床上使用的所有抗体都是 IgG 同种型。然而，IgA 同种型也可以通过与单体 IgA 的激活 Fc 受体 (FcαRI) 结合来引发强大的抗肿瘤反应。除了单核细胞、巨噬细胞和嗜酸性粒细胞等表达 FcαRI 的免疫细胞外，中性粒细胞在消除 IgA 调理的肿瘤细胞方面尤为活跃。然而，用 IgG 作为单一药物，我们通过肿瘤细胞杀伤的活细胞成像观察到，似乎几乎不可能有效地激活中性粒细胞。在这项研究中，我们研究了 Fc 受体的表达、结合和信号转导，以阐明为什么 IgA 触发中性粒细胞的效率比 IgG 高。中性粒细胞上 FcαRI 的表达约为 Fcγ 受体 FcγRIIa 和 FcγRIIIb 的 2 倍和 20 倍，但中性粒细胞与 IgA 或 IgG 包被表面的结合相似。此外，我们的数据表明，与 IgG 相比，IgA 介导的中性粒细胞结合更稳定。与 IgG 相比，IgA 与中性粒细胞的结合引发更强的 Fc 受体信号转导，这表明通过测量 p-ERK 信号分子来指示。我们提出，与 FcγRIIa 相比，IgA 与 FcαR/FcRγ 链复合物的更高化学计量比，激活四个 ITAMs（免疫受体酪氨酸基激活基序），再加上高度表达的 FcγRIIIb 可能起到诱饵作用，解释了为什么 IgA 比 IgG 更能有效地触发中性粒细胞杀伤肿瘤细胞。我们预计，通过使用 IgA 单克隆抗体利用大量中性粒细胞将是癌症治疗中抗体治疗武器库不断增长的宝贵补充。
