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脑癌患者的 Epstein-Barr 病毒和巨细胞病毒特异性免疫反应。

Epstein-Barr virus- and cytomegalovirus-specific immune response in patients with brain cancer.

机构信息

Department of Laboratory Medicine (LABMED), Karolinska Institutet, Stockholm, Sweden.

Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

出版信息

J Transl Med. 2018 Jul 3;16(1):182. doi: 10.1186/s12967-018-1557-9.

DOI:10.1186/s12967-018-1557-9
PMID:29970101
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6029420/
Abstract

BACKGROUND

Patients with brain tumor or pancreatic cancer exhibit the poorest prognosis, while immune fitness and cellular immune exhaustion impacts their survival immensely. This work identifies differences in the immune reactivity to the common human pathogens cytomegalovirus (CMV) and Epstein-Barr virus (EBV) between patients with brain tumor in comparison to those with pancreatic cancer and healthy individuals.

METHODS

We characterized the humoral and cellular immune responses of patients with brain tumor or pancreatic cancer to cytomegalovirus structural protein pp65 (CMV-pp65) as well as Epstein-Barr nuclear antigen-1 (EBNA-1) by whole-blood assay and ELISA.

RESULTS

Anti-CMV-pp65 plasma immunoglobulin gamma (IgG) titers were significantly lower in patients with brain tumor compared to healthy donors and patients with pancreatic cancer. Among the responding patients with GBM, those with a weak anti-CMV IgG response also had a decreased median overall survival (p = 0.017, 667 vs 419 days) while patients with brain tumor showed a generally suppressed anti-CMV immune-reactivity. Patients with brain tumor exhibited a significantly lower interferon gamma (IFNγ) response to EBNA-1 and CMV-pp65 compared to patients with pancreatic cancer or healthy donors. This antigen-specific response was further amplified in patients with brain tumor upon conditioning of whole blood with IL-2/IL-15/IL-21. Exclusively in this setting, among the responding patients with GBM, those exhibiting a EBV-specific cellular immune response above the median also displayed an increased median overall survival pattern compared to weak responders (753 vs 370 days, p < 0.001).

CONCLUSIONS

This report provides (i) a fast and easy assay using common viral antigens and cytokine stimulation to screen for immune fitness/exhaustion of patients with brain tumor in comparison to pancreatic cancer and healthy individuals and (ii) EBV/CMV-induced IFNγ production as a potential marker of survival in patients with brain tumor.

摘要

背景

患有脑肿瘤或胰腺癌的患者预后最差，而免疫适应性和细胞免疫衰竭对他们的生存有巨大影响。本研究旨在比较脑肿瘤患者与胰腺癌患者和健康个体之间对常见人类病原体巨细胞病毒（CMV）和 Epstein-Barr 病毒（EBV）的免疫反应差异。

方法

我们通过全血分析和 ELISA 对脑肿瘤或胰腺癌患者针对巨细胞病毒结构蛋白 pp65（CMV-pp65）和 Epstein-Barr 核抗原-1（EBNA-1）的体液和细胞免疫反应进行了表征。

结果

与健康供体和胰腺癌患者相比，脑肿瘤患者的抗 CMV-pp65 血浆免疫球蛋白 G（IgG）滴度明显降低。在 GBM 患者中，那些 CMV IgG 反应较弱的患者中位总生存期也较短（p=0.017，667 天 vs 419 天），而脑肿瘤患者表现出普遍抑制的抗 CMV 免疫反应。与胰腺癌患者或健康供体相比，脑肿瘤患者对 EBNA-1 和 CMV-pp65 的干扰素 γ（IFNγ）反应明显较低。在 IL-2/IL-15/IL-21 对全血进行预处理后，这种抗原特异性反应在脑肿瘤患者中进一步放大。仅在这种情况下，在具有 EBV 特异性细胞免疫反应高于中位数的 GBM 患者中，与弱反应者相比，中位总生存期也增加（753 天 vs 370 天，p<0.001）。

结论

本研究提供了（i）一种使用常见病毒抗原和细胞因子刺激快速简便的检测方法，用于筛查脑肿瘤患者与胰腺癌患者和健康个体之间的免疫适应性/衰竭，以及（ii）EBV/CMV 诱导的 IFNγ 产生作为脑肿瘤患者生存的潜在标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/7643e55dc05c/12967_2018_1557_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/7f2d94384d33/12967_2018_1557_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/355bb833bf91/12967_2018_1557_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/3b6def3fcc1a/12967_2018_1557_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/bfa73a49c22c/12967_2018_1557_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/7643e55dc05c/12967_2018_1557_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/7f2d94384d33/12967_2018_1557_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/355bb833bf91/12967_2018_1557_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/3b6def3fcc1a/12967_2018_1557_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/bfa73a49c22c/12967_2018_1557_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/13f4/6029420/7643e55dc05c/12967_2018_1557_Fig5_HTML.jpg

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