Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fc gamma receptors or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. Yet how these competing signals are integrated is poorly understood mechanistically, raising questions about how to effectively titrate immune responses. Here we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand on targets over a broad range of absolute molecular densities. Using endogenous as well as chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering this ratio reduces FcγR phosphorylation due to inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPα in vitro, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.

中文翻译：

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抗体：CD47比率通过竞争性受体磷酸化调节巨噬细胞吞噬作用

癌症免疫疗法通常通过引入激活Fcγ受体的靶向抗体或阻断破坏抑制性SIRPα-CD47结合的抗体来调节巨噬细胞效应子功能。然而，如何在机械上对这些竞争信号的整合方式却知之甚少，这引发了有关如何有效滴定免疫反应的疑问。在这里，我们发现巨噬细胞的吞噬决策受靶标上广泛的绝对分子密度范围内活化配体与抑制性配体之比的调节。使用内源性和嵌合受体，我们表明激活：抑制配体比率至少为10：需要1来促进模型抗体调理的CD47抑制的靶标的吞噬作用，降低该比例可降低FcγR磷酸化，这归因于募集到CD47结合的SIRPα的抑制性磷酸酶。我们证明比例信号对于肿瘤细胞的吞噬作用至关重要，并且可以通过在体外阻断SIRPα进行修饰，表明平衡靶向和阻断抗体对于控制巨噬细胞在癌症免疫疗法中的吞噬作用可能很重要。