慢性B细胞恶性肿瘤患者中普遍存在获得性T细胞功能障碍。鉴于T细胞代谢与功能之间的密切关系，我们调查了恶性细胞引起的T细胞功能障碍的代谢改变。我们首先使用B淋巴细胞恶性细胞株和人体外周血单核细胞（PBMCs）建立了一个模型，该模型重现了癌症引起的T细胞功能障碍的主要方面。来自慢性淋巴细胞性白血病（PGA-1，CII，Mec-1）细胞株的T细胞改变了T细胞代谢组，生成了伪缺氧状态，而其他B细胞恶性肿瘤细胞株没有这种改变。T细胞保持在有氧糖酵解状态，并不能转化为氧化磷酸化。此外，T细胞产生免疫抑制性腺苷，通过抑制激活来产生负面影响，阻断腺苷受体可以恢复其功能。接下来，我们发现原发性慢性淋巴细胞性白血病样T细胞中存在类似缺氧状态的特征。伪缺氧状态可以在体外清除原发性慢性淋巴细胞性白血病细胞后逆转，并且在使用组合疗法（Venetoclax和Obinutuzumab）减少白血病负担后，也可以恢复T细胞功能。总之，我们揭示了慢性淋巴细胞性白血病中与T细胞功能障碍相关的伪缺氧程序。调节缺氧和嘌呤途径可能有助于治疗恢复T细胞功能。 版权所有© 2023年美国血液学学会。

Acquired T-cell dysfunction is common in chronic B-cell malignancies. Given the strong connection between T-cell metabolism and function, we investigated metabolic alterations as the basis for T-cell dysfunction induced by malignant cells. Using B-cell malignant cell lines and human PBMCs, we first established a model which recapitulates major aspects of cancer-induced T-cell dysfunction. Cell lines derived from chronic lymphocytic leukemia (PGA-1, CII, Mec-1), but not from other B-cell malignancies, altered T-cell metabolome by generating a pseudohypoxic state. T cells were retained in aerobic glycolysis and were not able to switch to OXPHOS. Moreover, T cells produced immunosuppressive adenosine that negatively affected function by dampening activation, which could be restored by blocking of adenosine receptors. Subsequently, we uncovered a similar hypoxic-like signature in autologous T cells from primary CLL samples. Pseudohypoxia was reversible upon depletion of CLL cells ex vivo and, importantly, after in vivo reduction of the leukemic burden with combination therapy (Venetoclax and Obinutuzumab), restoring T-cell function. In conclusion, we uncover a pseudohypoxic program connected with T cell dysfunction in CLL. Modulation of hypoxia and the purinergic pathway might contribute to therapeutic restoration of T-cell function.Copyright © 2023 American Society of Hematology.