Decreased Survival After Combining Thoracic Irradiation and an Anti-PD-1 Antibody Correlated With Increased T-cell Infiltration Into Cardiac and Lung Tissues.
Decreased Survival After Combining Thoracic Irradiation and an Anti-PD-1 Antibody Correlated With Increased T-cell Infiltration Into Cardiac and Lung Tissues.
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DOI：
10.1016/j.ijrobp.2017.06.2452
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发表时间：
2017-12-01
期刊：
影响因子：
--
通讯作者：
Lu B
中科院分区：
文献类型：
--
作者：
Myers CJ;Lu B
肺癌是美国癌症相关死亡率的主要原因。放射治疗是一种常见的治疗方法，可对包括肺和心脏在内的重要器官造成急性损伤，但单独使用放射治疗的严重毒性相对罕见。最近加入治疗方案的是免疫疗法，例如抗PD-1抗体，其阻断对活化T细胞的抑制。与传统的放化疗方案相比，抗PD-1治疗和胸部放射联合治疗有可能改善局部晚期肺癌的结局，但尚未在临床前模型中研究这些治疗对非恶性肺组织的影响。6-8用抗PD-1抗体或对照IgG治疗一周大的C57 Bl/6小鼠，伴或不伴胸部放射（20 Gy），并监测存活率作为终点，以确定联合治疗可能导致的毒性增加。免疫细胞浸润到照射的心脏和肺组织进行了分析，通过流式细胞术和组织学。在辐射后21天，IgG +辐射组中70%的动物存活，显著高于抗PD-1 +辐射组（36%; p=0.0169）。与单独的抗PD-1抗体相比，联合治疗后心脏和肺组织中的T细胞计数均显著升高（心脏：6.1对22.4，p<0.001;肺：3.4对20.8，p<0.001）或对照IgG加辐射（心脏11.3 vs 22.4，p<0.05;肺12.2 vs 20.8，p<0.05）。组织学分析证实了单独抗PD-1抗体与抗体加照射的比较中的这种增加（心脏：464 vs 679个细胞/视野，p<0.001;肺：780 vs 1109，p<0.001）和对照IgG加放射或组合疗法（心脏：526 vs 679个细胞/视野，p<0.001;肺：848 vs 1109，p<0.05）。在临床前模型中，抗PD-1抗体和胸部照射的组合导致T细胞浸润到肺和心脏组织中并增加死亡率。我们得出结论，辐射损伤的健康组织更容易受到活化T细胞的进一步损伤。
Lung cancer is the leading cause of cancer-related mortality in the United States. Radiation, a common component of treatment, can cause acute damage to critical organs including the lungs and the heart, but the serious toxicities from radiotherapy alone is relatively rare. A recent addition to the treatment regimen is immunotherapy, such as anti-PD-1 antibody, which blocks the inhibition of activated T cells. Combining anti-PD-1 treatment and thoracic radiation has potential for improving the outcomes of locally advanced lung cancer over traditional chemoradiation regimens, but the effect of combining these therapies on non-malignant lung tissue has not yet been investigated in preclinical models. 6–8 week old C57Bl/6 mice were treated with either anti-PD-1 antibody or control IgG with or without thoracic radiation (20Gy), and survival was monitored as an end point to determine any potential increase of toxicity from the combination therapy. Immune cell infiltration into the irradiated cardiac and lung tissues was analyzed via flow cytometry and histologically. At 21 days post-radiation, 70% of animals in the IgG + radiation group survived, significantly more than the anti-PD-1 + radiation group (36%; p=0.0169). T cell counts were significantly elevated in both cardiac and pulmonary tissues after combination therapy as compared to anti-PD-1 antibody alone (heart: 6.1 vs 22.4, p<0.001; lung 3.4 vs 20.8, p<0.001) or control IgG plus radiation (heart 11.3 vs 22.4, p<0.05; lung 12.2 vs 20.8, p<0.05) in flow cytometric studies. Histologic analysis confirmed this increase in the comparison of anti-PD-1 antibody alone versus antibody plus irradiation (heart: 464 vs 679 cells per field, p<0.001; lung: 780 vs 1109, p<0.001) and control IgG plus radiation or combination therapy (heart: 526 vs 679 cells per field, p<0.001; lung: 848 vs 1109, p<0.05). Combining anti-PD-1 antibody and thoracic irradiation results in T cell infiltration into lung and heart tissue and increases mortality in a preclinical model. We conclude that healthy tissue damaged by irradiation is more susceptible to further damage by activated T cells.
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