Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen-targeting mAbs is mediated-at least partially-by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47-SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47-SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47-SIRPα interactions further enhances destruction of IgA antibody-opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cells in vivo In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47-SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47-SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.

中文翻译：

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CD47-SIRPα检查点抑制可增强IgA介导的嗜中性粒细胞对肿瘤细胞的杀伤作用。

针对肿瘤抗原或免疫细胞抑制性检查点的治疗性单克隆抗体（mAb）在癌症治疗中有效。越来越多的证据表明，这些靶向肿瘤抗原的mAb的治疗功效至少部分是由髓样效应细胞介导的，后者由CD47和SIRPα之间的先天免疫检查点相互作用控制。我们和其他人先前已证明，体内和体外IgG抗体抑制CD47-SIRPα相互作用可显着增强抗体依赖性细胞的吞噬作用和肿瘤细胞的细胞毒性。相同的可变区，但尚未研究CD47-SIRPα对IgA介导的杀伤的影响。这里，我们表明，对CD47-SIRPα相互作用的检查点抑制进一步增强了人嗜中性白细胞对IgA抗体调理癌细胞的破坏。对于多种肿瘤类型和针对不同抗原（即HER2 / neu和EGFR）的IgA抗体显示了这一点。因此，将针对HER2 / neu或EGFR的IgA抗体与SIRPα抑制结合起来可有效消灭体内癌细胞。在同基因体内模型中，消灭癌细胞主要是由粒细胞介导的，粒细胞被主动募集到肿瘤部位被SIRPα封锁。我们得出结论，CD47-SIRPα检查点抑制可进一步增强IgA介导的肿瘤细胞破坏。