Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.
Department of Immunology, University of Toronto, Toronto, ON, Canada.
Blood Adv. 2024 Jun 25;8(12):3013-3026. doi: 10.1182/bloodadvances.2023011739.
Allogeneic double-negative T cells (DNTs) are a rare T-cell subset that effectively target acute myeloid leukemia (AML) without inducing graft-versus-host disease in an allogeneic setting. A phase 1 clinical trial demonstrated the feasibility, safety, and potential efficacy of allogeneic DNT therapy among patients with relapsed AML. However, the molecular mechanisms of DNT-mediated cytotoxicity against AML remain elusive. Thus, we used a flow cytometry-based high throughput screening to compare the surface molecule expression profile on DNTs during their interaction with DNT-susceptible or -resistant AML cells and identified a tumor necrosis factor α (TNFα)-dependent cytotoxic pathway in DNT-AML interaction. TNFα secreted by DNTs, upon encountering susceptible AML targets, sensitized AML cells to DNT-mediated killing, including those otherwise resistant to DNTs. Mechanistically, TNFα upregulated ICAM-1 on AML cells through a noncanonical JAK1-dependent pathway. DNTs then engaged with AML cells more effectively through an ICAM-1 receptor, lymphocyte function-associated antigen 1, leading to enhanced killing. These results reveal a TNFα-JAK1-ICAM-1 axis in DNT-mediated cytotoxicity against AML to improve therapeutic efficacy.
异体双阴性 T 细胞（DNTs）是一种罕见的 T 细胞亚群，在异体环境中能有效靶向急性髓系白血病（AML），而不会引发移植物抗宿主病。一项 1 期临床试验证明了异体 DNT 治疗在复发 AML 患者中的可行性、安全性和潜在疗效。然而，DNT 介导的对 AML 的细胞毒性的分子机制仍不清楚。因此，我们使用基于流式细胞术的高通量筛选，比较了 DNT 与 DNT 易感或耐药 AML 细胞相互作用过程中表面分子表达谱，并在 DNT-AML 相互作用中鉴定出一个依赖于肿瘤坏死因子 α（TNFα）的细胞毒性途径。DNT 遇到易感 AML 靶标时分泌的 TNFα 使 AML 细胞对 DNT 介导的杀伤敏感，包括那些对 DNT 耐药的细胞。从机制上讲，TNFα 通过非经典的 JAK1 依赖性途径在上皮细胞上调细胞间黏附分子 1（ICAM-1）。然后，DNT 通过 ICAM-1 受体淋巴细胞功能相关抗原 1 更有效地与 AML 细胞结合，导致杀伤增强。这些结果揭示了 DNT 介导的针对 AML 的细胞毒性中的 TNFα-JAK1-ICAM-1 轴，以提高治疗效果。
