Mitigation of Checkpoint Inhibitor-Induced Autoimmune Hemolytic Anemia through Modulation of Purinergic Signaling

自身免疫性溶血性贫血 免疫学 FOXP3型 自身抗体 医学 癌症研究 生物 免疫系统 抗体
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
出处
期刊:Blood [American Society of Hematology]
被引量:1
标识
DOI:10.1182/blood.2024024230
摘要

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.

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