Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

中文翻译：

---

PD-1 通过细胞毒性 T 淋巴细胞调节辐射诱导的心脏毒性

简介：联合免疫检查点封锁导致罕见的自身免疫并发症，例如致命的心肌炎。最近批准的几种用于肺癌治疗的抗程序性死亡 1 (anti-PD-1) 药物促使正在进行的临床试验将 PD-1 抑制剂与胸部放疗直接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辐射诱发的心脏毒性 (RICT) 的风险，这在霍奇金病和乳腺癌患者中得到了充分证明。方法：在不合并胸部放射治疗的肺毒性的情况下研究心脏毒性，我们开发了一种技术，在小鼠模型中提供心脏照射 (CIR)，同时阻断 PD-1，通过使用生理测试和死亡率作为终点以及组织学分析来确定心脏毒性的存在。结果：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 为 0%（p = 0.023）。生理测试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 CD8 抗体消耗 CD8 阳性淋巴细胞可逆转急性死亡率，这表明毒性是 CD8 阳性细胞介导的。为了使用临床相关的分割放射治疗方案验证这些发现，我们通过每天提供 5 次 6 Gy 的剂量重复了这项研究。在接受分段放射治疗和同时抗 PD-1 治疗的小鼠中观察到类似的死亡率、心功能障碍和组织学变化。结论：本研究提供了强有力的临床前证据，表明辐射诱发的心脏毒性受 PD-1 轴的调节，PD-1 阻断剂应在仔细制定放射治疗计划的情况下进行，以减少心脏剂量。