Mitigation of checkpoint inhibitor–induced autoimmune hemolytic anemia through modulation of purinergic signaling

作者：Flavia Dei Zotti, Annie Qiu, Vivette D. D’Agati, Shwatina Jagnarine, Emmalene Kyritsis, Anabel Miller, Maria Tredicine, Daysha Fliginger, Elizabeth F. Stone, Sandhya R. Panch, Krystalyn E. Hudson · 发表于：Blood · 年份：2024 · DOI：10.1182/blood.2024024230 · 被引用次数：11 · 研究领域：Blood groups and transfusion、Immune Cell Function and Interaction、Complement system in diseases

ABSTRACT: Immune checkpoint inhibitors (ICPis) 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 AIHA secondary to ICPi therapy (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 (eg, autoantibodies, hemolysis, and increased mortality). During ICPi-AIHA, there is the simultaneous reduction of 2 regulatory T-cell populations (FoxP3+ and Tr1 [type 1 regulatory cells]) and an increase in inflammatory T helper cell 17 (TH17). Moreover, a novel CD39+CD73-FoxP3-CD25- CD4+ T-cell subset (ie, CD39 single positive [CD39SP]) emerges, and early increases in CD39SP predict AIHA development; CD39 is an ectonuclease that breaks down adenosine triphosphate (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, ICP...