Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Blood Adv. 2024 Sep 10;8(17):4633-4646. doi: 10.1182/bloodadvances.2023011934.
Autologous T-cell-based therapies, such as chimeric antigen receptor (CAR) T-cell therapy, exhibit low success rates in chronic lymphocytic leukemia (CLL) and correlate with a dysfunctional T-cell phenotype observed in patients. Despite various proposed mechanisms of T-cell dysfunction in CLL, the specific CLL-derived factors responsible remain unidentified. This study aimed to investigate the mechanisms through which CLL cells suppress CAR T-cell activation and function. We found that CLL-derived T cells get activated, albeit in a delayed fashion, and specifically that restimulation of CAR T cells in the presence of CLL cells causes impaired cytokine production and reduced proliferation. Notably, coculture of T cells with CD40-activated CLL cells did not lead to T-cell dysfunction, and this required direct cell contact between the CD40-stimulated CLL cells and T cells. Inhibition of kinases involved in the CD40 signaling cascade revealed that the Spare Respiratory Capacity (SRC) kinase inhibitor dasatinib prevented rescue of T-cell function independent of CD40-mediated increased levels of costimulatory and adhesion ligands on CLL cells. Transcriptome profiling of CD40-stimulated CLL cells with or without dasatinib identified widespread differential gene expression. Selecting for surface receptor genes revealed CD40-mediated downregulation of the Sialic acid-binding Ig-like lectin 10 (Siglec-10) ligands CD24 and CD52, which was prevented by dasatinib, suggesting a role for these ligands in functional T-cell suppression in CLL. Indeed, blocking CD24 and/or CD52 markedly reduced CAR T-cell dysfunction upon coculture with resting CLL cells. These results demonstrated that T cells derived from CLL patients can be reinvigorated by manipulating CLL-T-cell interactions. Targeting CD24- and CD52-mediated CLL-T-cell interaction could be a promising therapeutic strategy to enhance T-cell function in CLL.
自体 T 细胞疗法，如嵌合抗原受体（CAR）T 细胞疗法，在慢性淋巴细胞白血病（CLL）中的成功率较低，这与患者中观察到的功能失调的 T 细胞表型相关。尽管已经提出了 CLL 中 T 细胞功能障碍的各种机制，但具体的 CLL 衍生因素仍未确定。本研究旨在探讨 CLL 细胞抑制 CAR T 细胞激活和功能的机制。我们发现，CLL 衍生的 T 细胞虽然激活时间较晚，但确实会被激活，特别是在存在 CLL 细胞的情况下再刺激 CAR T 细胞会导致细胞因子产生减少和增殖减少。值得注意的是，T 细胞与 CD40 激活的 CLL 细胞共培养不会导致 T 细胞功能障碍，而这需要 CD40 刺激的 CLL 细胞与 T 细胞之间的直接细胞接触。参与 CD40 信号级联的激酶抑制剂的抑制作用表明，Spare Respiratory Capacity（SRC）激酶抑制剂 dasatinib 可防止 T 细胞功能的恢复，而与 CD40 介导的 CLL 细胞上共刺激和粘附配体水平的增加无关。用或不用 dasatinib 对 CD40 刺激的 CLL 细胞进行转录组谱分析，发现广泛的差异基因表达。选择表面受体基因表明，CD40 介导的 Siglec-10（Siglec-10）配体 CD24 和 CD52 的下调，而 dasatinib 可阻止这种下调，表明这些配体在 CLL 中功能性 T 细胞抑制中起作用。事实上，在与静止的 CLL 细胞共培养时，阻断 CD24 和/或 CD52 可显著减少 CAR T 细胞的功能障碍。这些结果表明，通过操纵 CLL-T 细胞相互作用，可以使源自 CLL 患者的 T 细胞恢复活力。靶向 CD24 和 CD52 介导的 CLL-T 细胞相互作用可能是增强 CLL 中 T 细胞功能的一种很有前途的治疗策略。
