由于供体的 T 细胞和 NK 细胞具有抗白血病活性，同种异体造血干细胞移植 (alloHSCT) 可以提高急性髓系白血病 (AML) 患者的生存率。然而，alloHSCT 的使用受到供体可用性、受者年龄和潜在严重副作用的限制。同样，由于白血病免疫逃逸的多种机制，引导自体 T 细胞对抗肿瘤细胞的免疫疗法（包括 T 细胞募集抗体、嵌合抗原受体 T 细胞疗法和免疫检查点抑制剂）的疗效在 AML 中受到限制。这促使人们寻找新的免疫刺激方法。在这里，我们发现小分子 GSK621 激活 AMP 激活蛋白激酶 (AMPK)（细胞能量平衡的主要调节因子）会诱导小鼠和人类 AML 细胞中的钙网蛋白 (CALR) 膜暴露。当 CALR 暴露在细胞表面时，它会作为损伤相关分子模式 (DAMP) 刺激免疫反应。我们发现GSK621处理的小鼠白血病细胞促进骨髓源性树突状细胞的活化和成熟。此外，接种经 GSK621 处理的白血病细胞对移植 AML 的同基因免疫功能正常受体具有保护作用。这种效应在 CD4/CD8 T 细胞耗尽的受体中消失。总之，这些结果表明 GSK621 激活 AMPK 会引发免疫原性细胞死亡的特征，并促进针对白血病的强大免疫反应。因此，药理学 AMPK 激活代表了改善 AML 免疫治疗活性的新潜在靶点。版权所有 © 2023 美国血液学会。

Survival of patients with acute myeloid leukemia (AML) can be improved by allogenic hematopoietic stem cell transplantation (alloHSCT) due to the anti-leukemic activity of T- and NK-cells from the donor. However, the use of alloHSCT is limited by donor availability, recipient age, and potential severe side effects. Similarly, the efficacy of immunotherapies directing autologous T-cells against tumor cells, including T-cell recruiting antibodies, chimeric antigen receptor T-cell therapy, and immune checkpoint inhibitors is limited in AML due to multiple mechanisms of leukemia immune escape. This has prompted a search for novel immunostimulatory approaches. Here, we show that activation of AMP-activated protein kinase (AMPK), a master regulator of cellular energy balance, by the small molecule GSK621 induces calreticulin (CALR) membrane exposure in murine and human AML cells. When CALR is exposed on the cell surface, it serves as a damage-associated molecular pattern (DAMP) that stimulates immune responses. We found that GSK621-treated murine leukemia cells promote the activation and maturation of bone marrow-derived dendritic cells. Moreover, vaccination with GSK621-treated leukemia cells had a protective effect in syngeneic immunocompetent recipients bearing transplanted AMLs. This effect was lost in recipients depleted of CD4/CD8 T cells. Together, these results demonstrate that AMPK activation by GSK621 elicits traits of immunogenic cell death and promotes a robust immune response against leukemia. Pharmacologic AMPK activation thus represents a new potential target for improving the activity of immunotherapy in AML.Copyright © 2023 American Society of Hematology.