Diamantina Institute, University of Queensland, Woolloongabba, QLD, Australia.
Cancer Services Unit, Department of Haematology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.
Front Immunol. 2021 Jan 21;11:610523. doi: 10.3389/fimmu.2020.610523. eCollection 2020.
Targeted antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. We have previously shown that resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), from CLL patients is characterized by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. In this regard, an innate immune checkpoint was recently described that uses the CD47:SIRPα axis to suppress phagocytic responses by macrophages. In this study we examine whether the SIRPα axis regulates ADP responses to the anti-CD20 antibody, obinutuzumab, by NLCs. Using siRNA depletion strategies we show that SIRPα is a suppressor of ADP responses. Moreover, we show that this innate immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPα suppression is mediated the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPα innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.
靶向抗体疗法改善了慢性淋巴细胞白血病 (CLL) 患者的预后。然而，耐药性常常会出现。我们之前已经表明，来自 CLL 患者的单核细胞衍生的巨噬细胞（称为类滋养细胞，NLC）对治疗性抗体的耐药性的特征在于抗体依赖性吞噬作用（ADP）的抑制。导致 ADP 反应减弱的机制仍未解决。在这方面，最近描述了一种先天免疫检查点，该检查点使用 CD47:SIRPα 轴来抑制巨噬细胞的吞噬反应。在这项研究中，我们检查了 SIRPα 轴是否通过 NLC 调节抗 CD20 抗体奥滨尤珠单抗的 ADP 反应。使用 siRNA 耗竭策略，我们表明 SIRPα 是 ADP 反应的抑制剂。此外，我们表明这种先天免疫检查点有助于源自 CLL 患者的 NLC 中的耐药表型。最后，我们表明 SIRPα 抑制是由磷酸酶 Shp1 介导的，它反过来抑制 ADP 依赖的 SYK 激活。因此，我们确定了一种可药物靶向的途径，可用于增强对 CLL 中使用的现有治疗性抗体的敏感性。这是第一项表明激活 CD47:SIRPα 先天免疫检查点有助于 CLL 患者的 NLC 中 ADP 耐药性的研究。
