PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes.
PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes.
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PD-1通过细胞毒性T淋巴细胞调节辐射诱导的心脏毒性。
DOI：
10.1016/j.jtho.2017.12.002
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发表时间：
2018-04
影响因子：
20.4
通讯作者：
Lu, Bo
中科院分区：
文献类型：
--
作者：
Du, Shisuo;Zhou, Lin;Alexander, Gregory S.;Park, Kyewon;Yang, Lifeng;Wang, Nadan;Zaorsky, Nicholas G.;Ma, Xinliang;Wang, Yajing;Dicker, Adam P.;Lu, Bo
联合免疫检查点阻断导致罕见的自身免疫并发症，如致命的心肌炎。最近批准的几种抗程序性死亡1（抗PD-1）药物用于肺癌治疗，促使正在进行的临床试验直接将联合收割机PD-1抑制剂与胸部放疗结合用于局部晚期肺癌。任何一种方式的重叠毒性都有可能增加放射性心脏毒性（RICT）的风险，这在霍奇金病和乳腺癌患者中有充分的记录。为了研究胸部放疗的心脏毒性而不引起复合肺毒性，我们开发了一种在小鼠模型中同时进行心脏照射（CIR）和PD-1阻断的技术，以通过使用生理测试和死亡率作为终点沿着组织学分析来确定心脏毒性的存在。我们观察到CIR加抗PD-1抗体后2周内的急性死亡率为30%，而CIR加免疫球蛋白G的急性死亡率为0%（p = 0.023）。生理学检查显示超声心动图显示左心室射血分数降低（p < 0.01）。组织分析显示心脏组织内免疫细胞浸润增加。用抗CD 8抗体耗竭CD 8阳性淋巴细胞可逆转急性死亡率，表明毒性是CD 8阳性细胞介导的。为了使用临床相关的分次放疗方案验证这些发现，我们重复了这项研究，每天给予5次6戈伊的分次放疗。在接受分次放疗与同时抗PD-1治疗的小鼠中观察到相似的死亡率、心功能障碍和组织学变化。这项研究提供了强有力的临床前证据，表明放射诱导的心脏毒性是由PD-1轴调节的，PD-1阻滞剂应与仔细的放射治疗计划一起使用，以减少心脏剂量。
Combined immune checkpoint blockade has led to rare autoimmune complications, such as fatal myocarditis. Recent approvals of several anti–programmed death 1 (anti–PD-1) drugs for lung cancer treatment prompted ongoing clinical trials that directly combine PD-1 inhibitors with thoracic radiotherapy for locally advanced lung cancer. Overlapping toxicities from either modality have the potential to increase the risk for radiation-induced cardiotoxicity (RICT), which is well documented among patients with Hodgkin’s disease and breast cancer. To investigate cardiotoxicity without the compounding pulmonary toxicity from thoracic radiotherapy, we developed a technique to deliver cardiac irradiation (CIR) in a mouse model concurrently with PD-1 blockade to determine the presence of cardiac toxicity by using physiological testing and mortality as end points along with histological analysis. We observed an acute mortality of 30% within 2 weeks after CIR plus anti–PD-1 antibody compared with 0% from CIR plus immunoglobulin G (p = 0.023). Physiological testing demonstrated a reduced left ventricular ejection fraction (p < 0.01) by echocardiogram. Tissue analyses revealed increased immune cell infiltrates within cardiac tissue. Depletion of CD8-positive lymphocytes with anti-CD8 antibody reversed the acute mortality, suggesting that the toxicity is CD8-positive cell-mediated. To validate these findings using a clinically relevant fractionated radiotherapy regimen, we repeated the study by delivering five daily fractions of 6 Gy. Similar mortality, cardiac dysfunction, and histological changes were observed in mice receiving fractionated radiotherapy with concurrent anti–PD-1 therapy. This study provides strong preclinical evidence that radiation-induced cardiotoxicity is modulated by the PD-1 axis and that PD-1 blockade should be administered with careful radiotherapy planning with an effort of reducing cardiac dose.
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影响因子：
51.1
作者：
Bradley, Jeffrey D.;Paulus, Rebecca;Komaki, Ritsuko;Masters, Gregory;Blumenschein, George;Schild, Steven;Bogart, Jeffrey;Hu, Chen;Forster, Kenneth;Magliocco, Anthony;Kavadi, Vivek;Garces, Yolanda I.;Narayan, Samir;Iyengar, Puneeth;Robinson, Cliff;Wynn, Raymond B.;Koprowski, Christopher;Meng, Joanne;Beitler, Jonathan;Gaur, Rakesh;Curran, Walter, Jr.;Choy, Hak
通讯作者：
Choy, Hak
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
程序性细胞死亡 1 缺陷导致 C57BL/6 小鼠心房重塑。
影响因子：
5.4
作者：
Fu, Guoqiang;Cao, Yizhan;Zheng, Qiangsun
通讯作者：
Zheng, Qiangsun
DOI：
10.1097/jto.0000000000000306
发表时间：
2014-10
期刊：
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
影响因子：
--
作者：
Gomez DR;Yusuf SW;Munsell MF;Welsh JW;Liao Z;Lin SH;Pan HY;Chang JY;Komaki R;Cox JD;McAleer MF;Grosshans DR
通讯作者：
Grosshans DR
影响因子：
5.9
作者：
BROSIUS, FC;WALLER, BF;ROBERTS, WC
通讯作者：
ROBERTS, WC