PD-1抑制剂对心肌炎症微环境及放射性损伤影响的实验研究

doi:10.3760/cma.j.cn113030-20201203-00587

摘要
图/表
参考文献(21)
相关文章 (15)
点击分布统计
下载分布统计

全文: PDF (0 KB) HTML (1 KB)
输出: BibTeX | EndNote (RIS) 背景资料

摘要目的从免疫微环境的角度初探PD-1抑制剂对小鼠心肌损伤的影响及其潜在机制。方法建立小鼠放射性心肌损伤(RIMI)模型,将20只C57BL/6小鼠随机分为4个组,每组5只。A组为对照组;B组为PD-1抑制剂组;C组为单纯照射组,心脏单次照射15Gy;D组为照射+PD-1抑制剂组。照射后1个月麻醉处死小鼠,HE和Masson染色观察心肌组织形态学改变和评估心肌纤维化;流式细胞术检测心肌CD⁺₃、CD⁺₃CD⁺₄、CD⁺₃CD₈淋巴细胞亚群及细胞因子(IL-4、IL-6、IL-17A、TNF-α、TGF-β1、INF-γ)水平;TUNEL检测心肌细胞凋亡率。结果照射后1个月,B组未见明显的心肌纤维化表现,C组和D组可见胶原纤维分布于心肌细胞间质。A、B、C、D组心肌胶原容积分数(CVF)分别为(1.97±0.36)%、(2.83±1.03)%、(5.39±0.77)%、(7.72±1.43)%,A组与B组间的CVF相似(P=0.314),其余各组间均不同(均P<0.05)。与A组比较,B、C、D组的CD⁺₃T淋巴细胞的绝对值和百分比均增高(均P<0.01),D组高于B组和C组(均P<0.01);A、C、B、D组的CD⁺₃CD⁺₄T淋巴细胞的绝对值和百分比相近(均P>0.05);D组的CD⁺₃CD⁺₈T淋巴细胞的绝对值和百分比都高于A、B、C组(P<0.001)。D组的IL-6、IL-17A、TGF-β1水平均高于A、B、C组(均P<0.001)。A、B、C、D组的凋亡指数逐渐增加,各组间比较差异均有统计学意义(均P<0.001)。结论 PD-1抑制剂可通过促进心肌免疫炎症反应加重RIMI。

	服务

	把本文推荐给朋友
	加入我的书架
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	周开艳
	刘凌枫
	曹丽
	王刚
	赵朝芬
	旷华香
	胡银祥
	张皓嘉
	苏胜发
	卢冰

关键词 ： PD-1抑制剂, 放射性心肌损伤, 小鼠

Abstract：Objective To explore the potential mechanism of PD-1 inhibitor P on RIMI from the perspective of immune microenvironment. Methods To establish a mouse model of radiation-induced myocardial injury (RIMI), twenty C57BL/6 mice were randomly divided into 4 groups, 5 in each group. Group A was the healthy control group;Group B was the PD-1 inhibitor group;Group C was the simple irradiation group, with a heart irradiation of 15Gy;Group D was the irradiation+ PD-1 inhibitor group. One month after irradiation, the mice were anesthetized and sacrificed. The morphological changes of myocardial tissues were observed by HE staining. The myocardial fibrosis was assessed by Masson staining. CD⁺₃, CD⁺₃CD⁺₄, CD⁺₃CD₈ lymphocyte subsets and cytokines (IL-4, IL-6, IL-17A, TNF-α, TGF-β1 and INF-γ) levels were determined by flow cytometry. The apoptosis rate of myocardial cells was detected by TUNE. Results One month after irradiation, there was no obvious myocardial fibrosis in group B, and collagen fibers were distributed in the interstitium of myocardial cells in groups C and D. Semi-quantitative analysis results showed that the myocardial collagen volume fraction (CVF) of groups A, B, C and D were (1.97±0.36)%,(2.83±1.03)%,(5.39±0.77)% and (7.72±1.43)%, respectively. The CVF between group A and group B was similar (P=0.314), and the differences in CVF between the other groups were statistically significant (all P<0.05). Compared with group A, the absolute value and percentage of CD⁺₃ T lymphocytes were significantly increased in groups B, C and D (all P<0.01). The values in group D were significantly higher than those in group B and group C (all P<0.01);The absolute value and percentage of CD⁺₃CD4 T lymphocytes were similar among four groups (all P>0.05);The absolute value and percentage of CD⁺₃CD₈ T lymphocytes in group D were significantly higher than those in groups A,B and C (all P<0.001). The expression levels of IL-6, IL-17A, and TGF-β1 in group D were significantly higher compared with those in groups A, B and C (all P<0.001). The apoptotic index was gradually increased in four groups, and the differences in apoptotic index among four groups were statistically significant (all P<0.001). Conclusion PD-1 inhibitors can aggravate RIMI by promoting myocardial immune inflammatory response.

Key words： PD-1 inhibitor Radiation-induced myocardial injury Mouse

收稿日期: 2020-12-03

基金资助:贵州省自然科学基金资助项目(黔科合基础[2020]1Y338);国家自然科学基金(81960548);贵州省肿瘤医院院级科技计划项目(YJ2019)

通讯作者: 苏胜发,Email:sushengfa2005@163.com

引用本文:

周开艳,刘凌枫,曹丽等. PD-1抑制剂对心肌炎症微环境及放射性损伤影响的实验研究[J]. 中华放射肿瘤学杂志, 2022, 31(1): 79-84.

Zhou Kaiyan,Liu Lingfeng,Cao Li et al. Experimentation of effect of PD-1 inhibitor on myocardial inflammation microenvironment and radiation-induced injury[J]. Chinese Journal of Radiation Oncology, 2022, 31(1): 79-84.

链接本文:

http://journal12.magtechjournal.com/Jweb_fszlx/CN/10.3760/cma.j.cn113030-20201203-00587 或 http://journal12.magtechjournal.com/Jweb_fszlx/CN/Y2022/V31/I1/79

[1] 郑荣寿,孙可欣,张思维,等,2015年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志,2019, 41(1):19-28. DOI:10.3760/cma.j.issn.0253-3766.2019.01.008.
ZHENG RS, SUN KX, ZHANG SW,et al. Report of cancer epidemiology in China, 2015[J]. Chin J Oncol, 2019, 41(1):19-28. DOI:10.3760/cma.j.issn.0253-3766.2019.01.008.
[2] GARON EB, RIZVI NA, HUI R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer[J]. N Engl J Med, 2015, 372(21):2018-2028. DOI:10.1056/NEJMoa1501824.
[3] MOK TSK, WU YL, KUDABA I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042):a randomised, open-label, controlled, phase 3 trial[J]. Lancet, 2019, 393(10183):1819-1830. DOI:10.1016/S0140-6736(18)32409-7.
[4] WEICHSELBAUM RR, LIANG H, DENG L, et al. Radiotherapy and immunotherapy:a beneficial liaison?[J]. Nat Rev Clin Oncol, 2017, 14(6):365-379. DOI:10.1038/nrclinonc.2016.211.
[5] GRAY JE, VILLEGAS A, DANIEL D, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC-update from PACIFIC[J]. J Thorac Oncol, 2020, 15(2):288-293. DOI:10.1016/j.jtho.2019.10.002.
[6] BERNSTEIN MB, KRISHNAN S, HODGE JW, et al. Immunotherapy and stereotactic ablative radiotherapy (ISABR):a curative approach?[J]. Nat Rev Clin Oncol, 2016, 13(8):516-524. DOI:10.1038/nrclinonc.2016.30.
[7] MOSLEHI JJ, SALEM JE, SOSMAN JA, et al. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis[J]. Lancet, 2018, 391(10124):933. DOI:10.1016/S0140-6736(18)30533-6.
[8] WANG H, WEI J, ZHENG Q, et al. Radiation-induced heart disease:a review of classification, mechanism and prevention[J]. Int J Biol Sci, 2019, 15(10):2128-2138. DOI:10.7150/ijbs.35460.
[9] ANTONIA SJ, VILLEGAS A, DANIEL D, et al. Overall survival with durvalumab after chemoradiotherapy in stage Ⅲ NSCLC[J]. N Engl J Med, 2018, 379(24):2342-2350. DOI:10.1056/NEJMoa1809697.
[10] DURM G, ALTHOUSE S, SADIQ A, et al. OA01.07 updated results of a phase Ⅱ trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage Ⅲ NSCLC[J]. J Thorac Oncol, 2018, 13:S321. DOI:10.1016/j.jtho.2018.08.238.
[11] THEELEN WSME, PEULEN HMU, LALEZARI F, et al. Effect of pembrolizumab after stereotactic body radiotherapy vs. pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer:results of the PEMBRO-RT phase 2 randomized clinical trial[J]. JAMA Oncol 2019, 5(9):1276-1282. DOI:10.1001/jamaoncol.2019.1478.
[12] LIN S, LIN X, CLAY D, et al. OA01.06 dETERRED:phase Ⅱ trial combining atezolizumab concurrently with chemoradiation therapy in locally advanced non-small cell lung cancer[J]. J Thorac Oncol, 2018, 13(10):S320-S321. DOI:10.1016/j.jtho.2018.08.237.
[13] PETERS S, FELIP E, DAFNI U, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage Ⅲ non-small cell lung cancer-The ETOP NICOLAS trial[J]. Lung Cancer, 2019, 133:83-87. DOI:10.1016/j.lungcan.2019.05.001.
[14] MYERS CJ, LU B. Decreased survival after combining thoracic irradiation and an anti-PD-1 antibody correlated with increased T-cell infiltration into cardiac and lung tissues[J]. Int J Radiat Oncol Biol Phys, 2017, 99(5):1129-1136. DOI:10.1016/j.ijrobp.2017.06.2452.
[15] DU S, ZHOU L, ALEXANDER GS, et al. PD-1 modulates radiation-induced cardiac toxicity through cytotoxic T lymphocytes[J]. J Thorac Oncol, 2018, 13(4):510-520. DOI:10.1016/j.jtho.2017.12.002.
[16] LÃUBLI H, BALMELLI C, BOSSARD M, et al. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma[J]. J Immunother Cancer, 2015, 3:11. DOI:10.1186/s40425-015-0057-1.
[17] JOHNSON DB, BALKO JM, COMPTON ml, et al. Fulminant myocarditis with combination immune checkpoint blockade[J]. N Engl J Med, 2016, 375(18):1749-1755. DOI:10.1056/NEJMoa1609214.
[18] DOVEDI SJ, CHEADLE EJ, POPPLE AL, et al. Fractionated radiation therapy stimulates antitumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD-1 blockade[J]. Clin Cancer Res, 2017, 23(18):5514-5526. DOI:10.1158/1078-0432. CCR-16-1673.
[19] SAIBIL SD, BONILLA L, MAJEED H, et al. Fatal myocarditis and rhabdomyositis in a patient with stage ⅠV melanoma treated with combined ipilimumab and nivolumab[J]. Curr Oncol, 2019, 26(3):e418-e421. DOI:10.3747/co.26.4381.
[20] BALDEVIANO GC, BARIN JG, TALOR MV, et al. Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy[J]. Circ Res, 2010, 106(10):1646-1655. DOI:10.1161/CIRCRESAHA.109.213157.
[21] LYMAN M, LIEUW V, RICHARDSON RT, et al. A bispecific antibody that targets IL-6 receptor and IL-17A for the potential therapy of patients with autoimmune and inflammatory diseases[J]. J Biol Chem, 2018, 293(24):9326-9334. DOI:10.1074/jbc. M117.818559.