Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies.
Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies.
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DOI：
10.3390/cancers13225725
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发表时间：
2021-11-16
期刊：
影响因子：
5.2
通讯作者：
Duda DG
中科院分区：
文献类型：
--
作者：
Gkika E;Adebahr S;Brenner A;Schimek-Jasch T;Radicioni G;Exner JP;Rühle A;Spohn SKB;Popp I;Zamboglou C;Sprave T;Firat E;Niedermann G;Nicolay NH;Nestle U;Grosu AL;Duda DG
放射治疗可通过触发趋化因子的释放以及改变肿瘤的血管内皮，促进细胞毒性T淋巴细胞的趋化作用，引发促炎和抗炎免疫反应，并改变肿瘤微环境。局部照射的这些效应可能具有全身性后果，并且可通过联合现有的免疫检查点抑制剂（ICBs）得到增强。对用于反应和毒性评估的微创血液生物标志物进行研究和验证，对于对可能从联合治疗中获益的患者进行分层至关重要。这项探索性前瞻性研究通过对一组血管生成和炎症的血液生物标志物进行纵向评估，评估了胸部放射治疗方法对免疫系统的影响。我们表明，循环中肿瘤坏死因子 -α、白细胞介素 -6和白细胞介素 -8水平的变化可能预示着放射治疗后免疫抑制的早期减轻。如果在更大规模的研究中得到验证，这些潜在的生物标志物可能有助于优化放射治疗与免疫检查点抑制剂联合使用的时间安排。
放射治疗对全身免疫的影响仍需以疾病特异性的方式进行全面描述。该研究的目的是在使用放射治疗胸部恶性肿瘤时检测全身免疫调节的潜在生物标志物。从56名胸部恶性肿瘤患者在放射治疗前（RT基线）、期间（RT期间）和结束时（RT结束）以及第一次（FU1）和第二次随访（FU2）采集系列血液样本。通过多重阵列测量白细胞介素 -10、干扰素 -γ、白细胞介素 -12p70、白细胞介素 -13、白细胞介素 -1β、白细胞介素 -4、白细胞介素 -6、白细胞介素 -8、肿瘤坏死因子 -α、碱性成纤维细胞生长因子、可溶性血管内皮生长因子受体 -1、胎盘生长因子、血管内皮生长因子、血管内皮生长因子 -C、血管内皮生长因子 -D和肝细胞生长因子的血清水平变化，并测试其与临床结果的关联。我们观察到在放射治疗期间和结束时，白细胞介素 -10、干扰素 -γ、胎盘生长因子和血管内皮生长因子 -D的水平升高，而白细胞介素 -8、血管内皮生长因子、血管内皮生长因子 -C和可溶性血管内皮生长因子受体 -1的水平降低。此外，肿瘤坏死因子 -α的基线浓度与总生存期（OS）显著相关。放射治疗结束时和随访1、2时的白细胞介素 -6水平与总生存期相关（放射治疗结束时：p = 0.039，风险比：1.041，95%置信区间：1.002 - 1.082，随访1：p = 0.001，风险比：1.139，95%置信区间：1.056 - 1.228，随访2：p = 0.017，风险比：1.101，95%置信区间：1.018 - 1.192），而白细胞介素 -8水平在放射治疗期间和结束时与总生存期相关（放射治疗期间：p = 0.017，风险比：1.014，95%置信区间：1.002 - 1.026，放射治疗结束时：p = 0.004，风险比：1.007，95%置信区间：1.061 - 1.686）。总之，肿瘤坏死因子 -α、白细胞介素 -6和白细胞介素 -8的血清水平是放射治疗反应的潜在生物标志物。鉴于免疫疗法最近在肺癌和食管癌中的应用，这些假定的血液生物标志物应在联合或序贯治疗环境中进一步验证和评估。
Radiation therapy can promote chemotaxis of cytotoxic T-lymphocytes by triggering the release of chemokines and altering the tumor’s vascular endothelium, triggering both pro- and anti-inflammatory immune responses and altering the tumor microenvironment. These effects of local irradiation may have systemic consequences and can be enhanced through the combination of available immune checkpoint blockers (ICBs). The study and validation of minimally invasive blood biomarkers for response and toxicity assessment are critical to stratify patients that would benefit from combination treatments. This exploratory prospective study evaluated the impact of thoracic radiotherapy approaches on the immune system using longitudinal assessment of a panel of blood biomarkers of angiogenesis and inflammation. We show that changes in circulating TNF-α, IL-6 and IL-8 levels could potentially indicate an early reduction in immunosuppression after radiotherapy. If validated in larger studies, these biomarker candidates might potentially help in optimally scheduling radiotherapy in combination with ICBs. The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1β, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002–1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056–1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018–1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002–1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061–1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.
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影响因子：
12.4
作者：
Ha H;Debnath B;Neamati N
通讯作者：
Neamati N
影响因子：
10.9
作者：
Keegan A;Ricciuti B;Garden P;Cohen L;Nishihara R;Adeni A;Paweletz C;Supplee J;Jänne PA;Severgnini M;Awad MM;Walt DR
通讯作者：
Walt DR
影响因子：
28.5
作者：
Ao X;Zhao L;Davis MA;Lubman DM;Lawrence TS;Kong FM
通讯作者：
Kong FM
影响因子：
4.7
作者：
Demaria S;Formenti SC
通讯作者：
Formenti SC
DOI：
10.1016/j.ijrobp.2005.05.032
发表时间：
2005-12-01
影响因子：
7
作者：
Hart, JP;Broadwater, G;Anscher, MS
通讯作者：
Anscher, MS