免疫检查点抑制剂（ICPi）彻底改变了癌症免疫疗法，但也可能诱发自身免疫性溶血性贫血（AIHA），这是一种死亡率很高的严重疾病。然而，除了通过减少检查点抑制来启动之外，ICPi-AIHA 的细胞和分子机制尚不清楚。在此，我们在一种新型小鼠模型中报告了 ICPi-AIHA，该模型显示出与已知人类 ICPi-AIHA 相似的特征（例如自身抗体、溶血、死亡率增加）。在 ICPi-AIHA 期间，两种调节性 T 细胞群（FoxP3 和 Tr1 Tregs）同时减少，而炎症性 TH17 T 细胞增加。此外，出现了一种新的 CD39 CD73-FoxP3-CD25-CD4 T 细胞亚群（即 CD39 单阳性 [CD39SP]），并且 CD39SP 的早期增加预示着 AIHA 的发展； CD39 是一种分解 ATP 的核酸外切酶。此外，我们发现通过注射重组腺苷三磷酸双磷酸酶来增强 ATP 酶活性可减轻 AIHA 的发展和显着的 CD39SP 减少，这两者都表明 CD39 的功能作用并证明了一种新的治疗方法。重要的是，CD39SP 在多种发生 AIHA 的小鼠模型和 AIHA 患者中均可检测到，证明其适用于特发性和继发性 AIHA。强调更广泛的自身免疫相关性，ICPi 治疗的 NZB 小鼠经历了狼疮（包括 AIHA）的加速发作和严重程度。此外，健康 B6 动物的 ICPi 治疗导致可检测到 CD39SP 并产生针对多种自身抗原（包括红细胞和血小板上的抗原）的自身抗体。总之，我们的研究结果阐明了 ICPi-AIHA 的细胞和分子机制，从而产生了具有转化潜力的新型诊断和治疗方法，可用于接受 ICPi 治疗的人类。版权所有 © 2024 美国血液学会。

Immune checkpoint inhibitors (ICPi) have revolutionized cancer immunotherapy but also can induce autoimmune hemolytic anemia (AIHA), a severe disease with high mortality. However, the cellular and molecular mechanism(s) of ICPi-AIHA are unclear, other than being initiated through decreased checkpoint inhibition. Herein, we report ICPi-AIHA in a novel mouse model that shows similar characteristics of known human ICPi-AIHA (e.g., autoantibodies, hemolysis, increased mortality). During ICPi-AIHA, there is the simultaneous reduction of two regulatory T cell populations (FoxP3+ and Tr1 Tregs) and an increase in inflammatory TH17 T cells. Moreover, a novel CD39+CD73-FoxP3-CD25- CD4+ T cell subset (i.e., CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down ATP. Additionally, we found that boosting ATPase activity by injecting recombinant apyrase mitigates AIHA development and significant CD39SP reductions, both suggesting a functional role for CD39 and demonstrating a novel therapeutic approach. Importantly, CD39SP are detectable in multiple mouse models developing AIHA and in patients with AIHA, demonstrating applicability to idiopathic and secondary AIHA. Highlighting broader autoimmunity relevance, ICPi-treated NZB mice experienced accelerated onset and severity of lupus, including AIHA. Moreover, ICPi treatment of healthy B6 animals led to detectable CD39SP and development of autoantibodies against multiple autoantigens including those on red blood cells and platelets. Together, our findings elucidate cellular and molecular mechanisms of ICPi-AIHA, leading to novel diagnostic and therapeutic approaches with translational potential for use in humans being treated with ICPi.Copyright © 2024 American Society of Hematology.