骨髓增生性肿瘤代表一组克隆性造血系统疾病，其中骨髓纤维化（MF）最具侵袭性。在骨髓肿瘤的背景下，人们越来越认识到免疫反应和 T 细胞功能的失调是疾病进展和免疫逃避的重要因素。我们研究了 MF 中的细胞毒性 T 细胞耗竭，以恢复针对恶性细胞的免疫反应。在 MF 患者的细胞毒性 T 细胞上观察到 CTLA-4 等抑制性受体表达增加，同时 IFNɣ 和 TNFɑ 分泌减少。 CTLA-4 配体 CD80 和 CD86 在 MF 粒细胞和单核细胞上增加，突出表明骨髓细胞在抑制 MF 患者 T 细胞活化方面可能发挥作用。与健康供体不同，来自 MF 患者的细胞毒性 T 细胞的激活在髓系细胞存在时减弱，而当 T 细胞单独培养或用抗 CTLA-4 治疗时恢复。此外，抗 CTLA-4 治疗促进了与细胞毒性 T 细胞共培养系统中肿瘤性单核细胞和粒细胞的消除。为了测试体内 CTLA-4 抑制作用，通过移植 MF CD34 细胞并在 NSGS 小鼠中输注同源 T 细胞来产生患者来源的异种移植物。 CTLA-4阻断减少了人类骨髓嵌合并导致脾脏和骨髓中的T细胞扩增。总体而言，这些发现揭示了 MF 中的 T 细胞功能障碍，并表明 CTLA-4 阻断可以增强细胞毒性 T 细胞介导的针对肿瘤细胞的免疫反应。© 2024 作者。 《美国血液学杂志》由 Wiley periodicals LLC 出版。

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.