Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Leukemia. 2024 Jun;38(6):1246-1255. doi: 10.1038/s41375-024-02255-1. Epub 2024 May 9.
T cells are important for the control of acute myeloid leukemia (AML), a common and often deadly malignancy. We observed that some AML patient samples are resistant to killing by human-engineered cytotoxic CD4 T cells. Single-cell RNA-seq of primary AML samples and CD4 T cells before and after their interaction uncovered transcriptional programs that correlate with AML sensitivity or resistance to CD4 T cell killing. Resistance-associated AML programs were enriched in AML patients with poor survival, and killing-resistant AML cells did not engage T cells in vitro. Killing-sensitive AML potently activated T cells before being killed, and upregulated ICAM1, a key component of the immune synapse with T cells. Without ICAM1, killing-sensitive AML became resistant to killing by primary ex vivo-isolated CD8 T cells in vitro, and engineered CD4 T cells in vitro and in vivo. While AML heterogeneity implies that multiple factors may determine their sensitivity to T cell killing, these data show that ICAM1 acts as an immune trigger, allowing T cell killing, and could play a role in AML patient survival in vivo.
T 细胞对于急性髓系白血病（AML）的控制至关重要，AML 是一种常见且通常致命的恶性肿瘤。我们观察到，一些 AML 患者样本对人类工程化的细胞毒性 CD4 T 细胞的杀伤具有抗性。对原发性 AML 样本和 CD4 T 细胞在相互作用前后的单细胞 RNA-seq 揭示了与 CD4 T 细胞杀伤的 AML 敏感性或抗性相关的转录程序。与 CD4 T 细胞杀伤抗性相关的 AML 程序在生存不良的 AML 患者中富集，并且体外杀伤抗性 AML 细胞不会与 T 细胞相互作用。杀伤敏感性 AML 在被杀伤之前强烈激活 T 细胞，并上调细胞间黏附分子 1（ICAM1），这是与 T 细胞形成免疫突触的关键组成部分。没有 ICAM1，体外杀伤敏感性 AML 对原发性离体分离的 CD8 T 细胞以及体外和体内工程化 CD4 T 细胞的杀伤变得具有抗性。虽然 AML 异质性意味着可能有多个因素决定其对 T 细胞杀伤的敏感性，但这些数据表明 ICAM1 作为免疫触发物发挥作用，允许 T 细胞杀伤，并可能在 AML 患者体内的生存中发挥作用。
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