Reducing Acute Myeloid Leukemia resistance to CAR T cell therapy by epigenetic activation of the tumor inflammasome-pyroptosis signaling

作者：Xin Huang, Qingrong Huang, Ciril Abraham, Mimi Chen, Ying Wang, Yuanyuan Tian, Yongping Zhang, Gennaro Calendo, Jean‐Pierre J. Issa, Yi Zhang · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-5901 · 被引用次数：1 · 研究领域：Inflammasome and immune disorders、Phagocytosis and Immune Regulation、Immune Cell Function and Interaction

Abstract Acute myeloid leukemia (AML) faces major clinical challenges characterized by high relapse and low cure rates. Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment for B cell malignancies, but it has limited efficacy in treating AML. Poor anti-tumor efficacy is often attributed to tumor resistance mechanisms and T cell dysfunction. The dysregulation of cell death in tumor cells plays a crucial role in promoting tumor resistance to immunotherapies. However, effective strategies that can disrupt this resistance mechanism remain an unmet need. Immunogenic cell death, such as pyroptosis, promotes effective innate and adaptive immunity. Pyroptosis is triggered by inflammasome activation and executed by caspase (CASP) and gasdermin (GSDM) proteins. Here we demonstrate that a previously unrecognized role of the NLRP3 inflammasome-pyroptosis signaling in sensitizing AML cells to CAR T cell killing. To test the hypothesis that epigenetic therapy agents that can activate the inflammasome-pyroptosis signaling in target tumor cells could potentially enhance therapeutic efficacy of CAR T cells against AML, we used a hypothesis-driven drug screening assay and identified that the DNA methylation inhibitor decitabine (DAC) induced high levels NLRP3 in murine AML C1498 cells. Bulk RNA-sequencing (RNA-seq) analysis revealed that DAC pre-treatment of murine C1498 AML cells induced expression of genes that were associated with inflammasomes and cell death mole...