PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice
PD-1 antibody and ruxolitinib enhances graft-versus-lymphoma effect without increasing acute graft-versus-host disease in mice
复制标题
PD-1 抗体和鲁索替尼增强小鼠移植物抗淋巴瘤效应，而不增加小鼠急性移植物抗宿主病
DOI：
10.1111/ajt.16275
复制
发表时间：
2020-09-05
影响因子：
8.8
通讯作者：
Xu, Kailin
中科院分区：
文献类型：
--
作者：
Pan, Bin;Shang, Longmei;Xu, Kailin
用检查点抑制剂增强移植后T细胞免疫应答增加了移植物抗淋巴瘤（GVL）效应，代价是增加急性移植物抗宿主病（aGVHD）。需要联合靶向治疗来减少检查点通道诱导的aGVHD而不损害GVL。我们研究了是否可以通过在同种异体移植小鼠模型中同时给予抗PD-1抗体和鲁索替尼来避免这种竞争，在该模型中，接受者用A20或EL 4淋巴瘤细胞进行攻击。单独给予PD-1抗体增加了GVL，但由于aGVHD的死亡增加，因此没有改善用A20细胞攻击的受体的存活。添加ruxolitinib降低了效应T细胞和相关细胞因子的水平。与Tbx 21（+）T细胞相比，Tbx 21（-）T细胞具有更高的PD-1水平。Ruxolitinib通过抑制Tbx 21表达增加供体T细胞上的PD-1水平。Ruxolitinib增加T细胞的凋亡，这被PD-1抗体逆转。PD-1抗体保留了颗粒酶B的表达和被鲁索替尼降低的T细胞的细胞毒性。联合治疗的最终结果是GVL增加，aGVHD没有增加，生存率增加。联合治疗改善了受表达高水平PD-L1的A20细胞攻击的受体的存活率，但对不表达PD-L1的EL 4细胞没有改善。
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.