Blood Diseases Institute, Xuzhou Medical University, Xuzhou, China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, China.
Am J Transplant. 2021 Feb;21(2):503-514. doi: 10.1111/ajt.16275. Epub 2020 Sep 5.
Boosting T cell immune response posttransplant with checkpoint inhibitors increases graft-versus-lymphoma (GVL) effects at the cost of increasing acute graft-versus-host disease (aGVHD). A combined targeted therapy is needed to decrease checkpoint inhibitors-induced aGVHD without impairing GVL. We studied whether this competition could be avoided by giving concurrent anti-PD-1 antibody and ruxolitinib in allotransplant mouse models in which recipients were challenged with A20 or EL4 lymphoma cells. Given alone the PD-1 antibody increased GVL but did not improve survival of recipients challenged with A20 cells because of increased deaths from aGVHD. Adding ruxolitinib decreased levels of effector T cells and related cytokines. Tbx21 T cells had higher PD-1 levels compared with Tbx21 T cells. Ruxolitinib increased PD-1 levels on donor T cells by suppressing Tbx21 expression. Ruxolitinib increased apoptosis of T cells which was reversed by the PD-1 antibody. PD-1 antibody preserved expression of granzyme B and cytotoxicity of T cells which were decreased by ruxolitinib. The net result of combined therapy was increased GVL, no increase in aGVHD and increased survival. The combined therapy improved survival of recipients challenged by A20 cells which expressed high level of PD-L1, but not EL4 cells which do not express PD-L1.
移植后使用检查点抑制剂增强 T 细胞免疫应答会增加移植物抗淋巴瘤（GVL）效应，但会增加急性移植物抗宿主病（aGVHD）的风险。需要联合靶向治疗来降低检查点抑制剂诱导的 aGVHD，同时不影响 GVL。我们研究了在接受 A20 或 EL4 淋巴瘤细胞挑战的同种异体移植小鼠模型中，同时给予抗 PD-1 抗体和鲁索利替尼是否可以避免这种竞争。单独使用 PD-1 抗体可增加 GVL，但不能改善接受 A20 细胞挑战的受者的生存率，因为 aGVHD 导致的死亡率增加。添加鲁索利替尼可降低效应 T 细胞和相关细胞因子的水平。与 Tbx21 T 细胞相比，Tbx21 T 细胞具有更高的 PD-1 水平。鲁索利替尼通过抑制 Tbx21 表达增加供体 T 细胞上的 PD-1 水平。鲁索利替尼增加了 T 细胞的凋亡，而 PD-1 抗体则逆转了这种凋亡。PD-1 抗体可维持 T 细胞中颗粒酶 B 的表达和细胞毒性，而鲁索利替尼则降低了这些细胞毒性。联合治疗的净结果是增加了 GVL，aGVHD 没有增加，生存率提高。联合治疗改善了表达高水平 PD-L1 的 A20 细胞挑战受者的生存率，但对不表达 PD-L1 的 EL4 细胞没有影响。
