血管内皮生长因子和程序性死亡分子配体1在肺鳞癌组织中的表达及对预后的影响
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摘要
目的探讨程序性死亡分子配体1(PD-L1)和血管内皮生长因子(VEGF)在肺鳞癌组织中的表达以及对总生存时间(OS)的影响。方法收集2004年7月至2009年6月75例肺鳞癌患者术后病理组织并构建组织芯片,采用SP法对VEGF和PD-L1进行免疫组化染色,采用Cox风险回归模型进行预后分析。同时提取癌症基因组数据库(TCGA)中肺鳞癌的相关数据,分析VEGF和PD-L1 mRNA表达水平与OS的关系。结果 75例肺鳞癌患者的中位OS为57.0个月。单因素分析显示,年龄、临床分期和VEGF评分与OS有关(P<0.05)。Cox多因素分析显示,VEGF评分和临床分期为影响OS的独立因素(P<0.05)。44例VEGF高评分者的中位OS为59.0个月,26例低评分者的中位OS未达到(P=0.008)。30例PD-L1高评分者的中位OS为74.0个月,45例低评分者为76.0个月(P=0.378)。在PD-L1高评分的患者中,22例VEGF高评分者的中位OS为43.0个月,8例VEGF低评分者的中位OS未达到(P=0.026)。共提取TCGA数据库中肺鳞癌患者449例,224例VEGF低表达者的中位OS为63.7个月,225例高表达者为39.6个月(P=0.222);225例PD-L1低表达者的中位OS为44.9个月,224例高表达者为61.4个月(P=0.451)。在224例PD-L1高表达的患者中,126例VEGF低表达者的中位OS为69.5个月,显著优于98例VEGF高表达者的38.5个月(P=0.033)。结论 VEGF表达与肺鳞癌患者的OS有关,同时高表达PD-L1和VEGF的患者预后不良。
Objective To investigate the expression of programmed death-ligand 1(PD-L1) and vascular endothelial growth factor(VEGF) in lung squamous cell carcinoma and its effect on overall survival(OS). Methods From July 2004 to June 2009, 75 patients with lung squamous cell carcinoma were enrolled and the tissue microarray was constructed. Immunohistochemical staining of VEGF and PD-L1 was performed by SP method. Prognostic analysis was performed by Cox regression model. Simultaneously, the data of lung squamous cell carcinoma in The Cancer Genome Database(TCGA) were extracted, and the association between the mRNA expression levels of VEGF and PD-L1 and OS was analyzed. Results The median OS of 75 patients with lung squamous cell carcinoma was 57.0 months. In univariate analysis using Cox proportional hazards model, age, clinical stage and VEGF score were associated with OS statistically(P<0.05). And in multivariate analysis, VEGF score and clinical stage were independent factors affecting OS(P<0.05). The median OS of 44 patients with VEGF high score was 59.0 months, and the median OS of 26 patients with VEGF low score did not reach(P=0.008). The median OS of 30 patients with PD-L1 high score was 74.0 months, and that of 45 patients with PD-L1 low score was 76.0 months(P=0.378). Among the patients with PD-L1 high score, the median OS of 22 patients with VEGF high score was 43.0 months, and that of 8 patients with VEGF low score did not reach(P=0.026). A total of 449 patients with lung squamous cell carcinoma were enrolled in the TCGA database. The median OS of 224 patients with low VEGF expression was 63.7 months, better than 39.6 months of 225 patients with high expression(P=0.222). The median OS of 225 patients with low PD-L1 expression was 44.9 months, shorter than 61.4 months of 224 patients with high expression(P=0.451). Among 224 patients with high PD-L1 expression, the median OS of 126 patients with low VEGF expression was 69.5 months, significantly better than 38.5 months of 98 patients with high VEGF expression(P=0.033). Conclusion The expression of VEGF is associated with OS in patients with lung squamous cell carcinoma, and patients with both high expression of PD-L1 and VEGF have a poor prognosis.
Objective To investigate the expression of programmed death-ligand 1(PD-L1) and vascular endothelial growth factor(VEGF) in lung squamous cell carcinoma and its effect on overall survival(OS). Methods From July 2004 to June 2009, 75 patients with lung squamous cell carcinoma were enrolled and the tissue microarray was constructed. Immunohistochemical staining of VEGF and PD-L1 was performed by SP method. Prognostic analysis was performed by Cox regression model. Simultaneously, the data of lung squamous cell carcinoma in The Cancer Genome Database(TCGA) were extracted, and the association between the mRNA expression levels of VEGF and PD-L1 and OS was analyzed. Results The median OS of 75 patients with lung squamous cell carcinoma was 57.0 months. In univariate analysis using Cox proportional hazards model, age, clinical stage and VEGF score were associated with OS statistically(P<0.05). And in multivariate analysis, VEGF score and clinical stage were independent factors affecting OS(P<0.05). The median OS of 44 patients with VEGF high score was 59.0 months, and the median OS of 26 patients with VEGF low score did not reach(P=0.008). The median OS of 30 patients with PD-L1 high score was 74.0 months, and that of 45 patients with PD-L1 low score was 76.0 months(P=0.378). Among the patients with PD-L1 high score, the median OS of 22 patients with VEGF high score was 43.0 months, and that of 8 patients with VEGF low score did not reach(P=0.026). A total of 449 patients with lung squamous cell carcinoma were enrolled in the TCGA database. The median OS of 224 patients with low VEGF expression was 63.7 months, better than 39.6 months of 225 patients with high expression(P=0.222). The median OS of 225 patients with low PD-L1 expression was 44.9 months, shorter than 61.4 months of 224 patients with high expression(P=0.451). Among 224 patients with high PD-L1 expression, the median OS of 126 patients with low VEGF expression was 69.5 months, significantly better than 38.5 months of 98 patients with high VEGF expression(P=0.033). Conclusion The expression of VEGF is associated with OS in patients with lung squamous cell carcinoma, and patients with both high expression of PD-L1 and VEGF have a poor prognosis.
引文
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[16] Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer[J]. Cancer Res, 2010, 70(15): 6171-6180.
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[2] Latchman YE, Liang SC, Wu Y, et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells[J]. Proc Natl Acad Sci U S A, 2004, 101(29): 10691-10696.
[3] Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(2): 123-135.
[4] Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer[J]. N Engl J Med, 2015, 373(17): 1627-1639.
[5] Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer[J]. N Engl J Med, 2016,375(19):1823-1833.
[6] Ramalingam SS, Dahlberg SE, Langer CJ, et al. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599[J]. J Clin Oncol, 2008, 26(1): 60-65.
[7] Voron T, Marcheteau E, Pernot S, et al. Control of the immune response by pro-angiogenic factors[J/OL]. Front Oncol, 2014[2018-05-20]. https://www.ncbi.nlm.nih.gov/pubmed/24765614.
[8] Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial[J]. Lancet, 2007, 370(9605): 2103-2111.
[9] Li P, Wang X, Liu Z, et al. Single nucleotide polymorphisms in CBLB, a regulator of T-cell response, predict radiation pneumonitis and outcomes after definitive radiotherapy for non-small-cell lung cancer[J]. Clin Lung Cancer, 2016, 17(4): 253-262.
[10] Li Q, Hou J, Hu Z, et al. Multiple mutations of lung squamous cell carcinoma shared common mechanisms[J]. Oncotarget, 2016,7(48):79629-79636.
[11] Luo X, Zang X, Yang L, et al. Comprehensive computational pathological image analysis predicts lung cancer prognosis[J]. J Thorac Oncol, 2016,12(3):501-509.
[12] Azuma K, Ota K, Kawahara A, et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer[J]. Ann Oncol, 2014, 25(10): 1935-1940.
[13] Chatterjee S, Heukamp LC, Siobal M, et al. Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer[J]. J Clin Invest, 2013, 123(4): 1732-1740.
[14] Ameratunga M, Asadi K, Lin X, et al. PD-L1 and tumor infiltrating lymphocytes as prognostic markers in resected NSCLC[J/OL]. PLoS One, 2016[2018-05-18]. https://www.ncbi.nlm.nih.gov/pubmed/27104612.
[15] Wallin JJ, Bendell JC, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma[J/OL]. Nat Commun, 2016[2018-05-15]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013615.
[16] Shrimali RK, Yu Z, Theoret MR, et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer[J]. Cancer Res, 2010, 70(15): 6171-6180.
[17] Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J]. N Engl J Med, 2018, 378(24): 2288-2301.
[18] Tada Y, Togashi Y, Kotani D, et al. Targeting VEGFR2 with ramucirumab strongly impacts effector/activated regulatory T cells and CD8(+) T cells in the tumor microenvironment[J/OL]. J Immunother Cancer, 2018[2018-11-20]. https://link.springer.com/article/10.1186/s40425-018-0403-1.