Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation.
Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation.
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DOI：
10.1016/j.celrep.2021.109587
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发表时间：
2021-08-24
期刊：
影响因子：
8.8
通讯作者：
Fletcher DA
中科院分区：
文献类型：
--
作者：
Suter EC;Schmid EM;Harris AR;Voets E;Francica B;Fletcher DA
肿瘤免疫治疗通常通过引入靶向抗体来激活Fcγ受体(FcγR)或阻断抗体来阻断抑制α与CD47的结合来调节巨噬细胞效应器的功能。然而，人们对这些相互竞争的信号是如何整合的知之甚少，这引发了如何有效地滴定免疫反应的问题。在这里，我们发现巨噬细胞的吞噬决定是由激活配体和抑制配体的比率在很大的绝对分子密度范围内调节的。同时使用内源性和嵌合受体，我们发现激活：抑制配体的比例至少为10：1才能促进模型抗体调理的CD47抑制靶的吞噬作用，降低这一比例会减少FcγR的磷酸化，因为CD47结合的Sirpα招募了抑制磷酸酶。我们证明比率测量信号对于肿瘤细胞的吞噬至关重要，并且可以通过阻断Sirpα来改变，这表明在癌症免疫治疗中平衡靶向和阻断抗体对于控制巨噬细胞的吞噬作用可能是重要的。Suter等人。使用重组的细胞样颗粒来定量探测巨噬细胞如何整合激活Fc受体和抑制Sirpα的同时信号。作者表明，抗体：CD47在靶标上的比例改变了竞争Syk激酶和SHP1磷酸酶在界面上的相对浓缩，最终决定了吞噬作用。
Cancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fcγ receptors (FcγRs) or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. However, how these competing signals are integrated is poorly understood, 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 over a broad range of absolute molecular densities. Using both endogenous and 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 that ratio reduces FcγR phosphorylation because of 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, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy. Suter et al. use reconstituted cell-like particles to quantitatively probe how macrophages integrate simultaneous signals from activating Fc receptors and inhibitory SIRPα. The authors show that the ratio of antibody:CD47 on the target changes relative enrichment of competing Syk kinase and SHP1 phosphatase at the interface, ultimately dictating phagocytosis.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.4
作者：
Graf, Beth;Bushnell, Timothy;Miller, Jim
通讯作者：
Miller, Jim
大小依赖性分离控制巨噬细胞对抗体调理靶标的吞噬作用。
影响因子：
64.5
作者：
Bakalar MH;Joffe AM;Schmid EM;Son S;Podolski M;Fletcher DA
通讯作者：
Fletcher DA
DOI：
10.1084/jem.186.7.1027
发表时间：
1997-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Crowley MT;Costello PS;Fitzer-Attas CJ;Turner M;Meng F;Lowell C;Tybulewicz VL;DeFranco AL
通讯作者：
DeFranco AL
影响因子：
7.5
作者：
Dustin, Michael L.
通讯作者：
Dustin, Michael L.