Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade.
Autoantibodies Drive Heart Damage Caused by Concomitant Radiation and PD-1 Blockade.
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自身抗体会导致伴随放射和 PD-1 阻断引起的心脏损伤。
DOI：
10.1158/2326-6066.cir-21-0839
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发表时间：
2023
影响因子：
10.1
通讯作者：
Lu,Bo
中科院分区：
文献类型：
--
作者：
Yan,Bo;Hooper,DCraig;Yuan,Zhiyong;Wang,Changli;Chen,Yulong;Lu,Bo
尽管存在潜在的心脏毒性重叠风险，PD-1阻断和胸部放射治疗正在局部晚期非小细胞肺癌和小细胞肺癌的临床试验中进行研究。我们之前的研究表明，在小鼠模型中，同时给予心脏照射和抗pd -1的心脏毒性是CD8+ t细胞依赖性的。本研究的目的是确定体液免疫是否有助于观察到的心脏组织损伤，通过肌酸激酶MB和心肌肌钙蛋白1释放和心功能下降来测量。在目前的研究中，我们证明了心脏自身抗体的存在，这是联合治疗中发生心脏毒性所必需的。接受心脏照射的小鼠，在接受抗pd -1治疗的同时，产生了高水平的抗体，这些抗体在体内与心脏组织和体外与心脏抗原反应。此外，缺乏B细胞的小鼠可以防止心脏毒性，而接受联合治疗的小鼠的含有自身抗体的血清在暴露于心脏照射的小鼠中复制了相同的病理表型，但在正常受体中没有观察到。血清的心脏毒性作用与心脏组织中CD8+ t细胞的积累有关，但由于IgG的消耗而受到限制。总之，心脏同时照射和PD-1阻断可导致心脏自身抗体的产生，这可能是由于被照射心脏组织内的抗原暴露，这在由此产生的心脏毒性中起关键作用。
Concurrent PD-1 blockade and thoracic radiotherapy is being investigated in clinical trials for locally advanced, non–small cell lung cancer and small cell lung cancer, despite a potential overlapping risk of cardiotoxicity. Our prior studies demonstrate that cardiotoxicity from concurrent cardiac irradiation and anti–PD-1 administration in a mouse model is CD8+T-cell dependent. The objective of this study was to determine whether humoral immunity contributed to the observed cardiac tissue damage, as measured by creatine kinase MB and cardiac troponin 1 release and decline in cardiac function. In the current study, we demonstrate the presence of cardiac autoantibodies, which were essential for the occurrence of cardiotoxicity from the combined therapy. Mice subjected to cardiac irradiation, while being treated with anti–PD-1, developed high levels of antibodies that reacted with cardiac tissuesin vivoand cardiac antigensin vitro. Moreover, mice deficient in B cells were protected against cardiotoxicity, whereas the transfer of autoantibody-containing sera from mice that had received combined treatment reproduced the same pathologic phenotype in mice exposed to cardiac irradiation but was not observed in normal recipients. The cardiotoxic effect of the sera, which associated with CD8+T-cell accumulation in cardiac tissue, was limited by IgG depletion. In conclusion, concurrent cardiac irradiation and PD-1 blockade leads to production of cardiac autoantibodies, likely due to antigen exposure within the irradiated cardiac tissues, which play a key role in the resulting cardiotoxicity.