目的:分析内蒙古中西部地区肺癌患者程序性细胞死亡1配体(programmed cell death ligand 1, PD-L1)的表达情况,探讨非小细胞肺癌(non-small cell lung cancer, NSCLC)患者中PD-L1的表达与驱动基因相关性。方法:采用免疫组织化学法(immunohistochemical, IHC)检测2021年1月-2023年8月内蒙古中西部地区792例肺癌患者组织标本中PD-L1表达(包括手术和穿刺标本),按照肿瘤细胞阳性比例评分(TPS评分)标准评分后进行统计分析。采用荧光PCR方法对其中的180例NSCLC患者的表皮生长因子受体 (epidermal growth factor receptor, EGFR)和间变性淋巴瘤激酶 (anaplastic lymphoma kinase, ALK)等10个驱动基因进行突变检测,与PD-L1表达进行相关性分析。结果:PD-L1在肺癌中阳性率为40.15%,其中,肺腺癌中阳性率为29.01%,肺鳞癌中阳性率为68.28%,小细胞肺癌中仅22.22%,且PD-L1表达与年龄、吸烟史、淋巴结转移、病理学分型和分化程度等呈正相关性(P＜0.05),与性别和分期无相关性(P＞0.05)。180例NSCLC标本中PD-L1表达阳性率为35%,均与EGFR表达呈正相关(P＜0.05);与其他驱动基因如ALK、ROS-1、MET、K-RAS、B-RAF、N-RAS、RET和HER-2均无相关性(P＞0.05)。结论:PD-L1在肺癌中表达存在异质性,且在NSCLC患者中,PD-L1的表达和EGFR驱动基因突变呈正相关,对NSCLC患者个体化靶向治疗提供了重要依据。
Objective: To analyze the expression of programmed cell death 1 (PD-L1) in patients with lung cancer in the central and western regions of Inner Mongolia, and to further explore the correlation between PD-L1 expression and driver genes in patients with non-small cell lung cancer (NSCLC). Methods: Immunohistochemical (IHC) method was used to detect the expression of PD-L1 (including surgical and puncture specimens) in 792 lung cancer patients in central and western Inner Mongolia from January 2018 to June 2021. After scoring according to TPS scoring standard, statistical analysis was carried out. The mutations of ten driving genes such as EGFR, ALK and ROS-1 in 180 patients with NSCLC were detected by fluorescence PCR, and then the correlation with the expression of PD-L1 was analyzed. Results: The positive rate of PD-L1 in lung cancer was 40.15%, of which the positive rate in lung adenocarcinoma was 29.01%, the positive rate in lung squamous cell carcinoma was 68.28%, and the positive rate in small cell lung cancer was only 22.22%. The expression of PD-L1 was positively correlated with age, smoking history, lymph node metastasis, pathological classification and differentiation (P＜0.05), and no correlation with gender and stage (P＞0.05). The positive rate of PD-L1 expression in 180 NSCLC specimens was 35 %, and it was positively correlated with EGFR expression (P＜0.05), but there was no correlation with other driver genes such as ALK, ROS-1, MET, K-RAS, B-RAF, N-RAS, RET and HER-2 (P＞0.05). Conclusion: There is heterogeneity in the expression of PD-L1 in lung cancer, and in NSCLC patients, the expression of PD-L1 is positively correlated with EGFR driver gene mutations, which provides an important basis for the individualized of targeted therapy for NSCLC patients.
[1] Patsoukis N, Weaver JD, Strauss L, et al. Immunometabolic regulations mediated by coinhibitory receptors and their impact on T cell immune responses[J]. Front Immunol, 2017, 8: 330.
[2] Giraldo NA, Nguyen P, Engle EL, et al. Multidimensional, quantitative assessment of PD-1/PD-L1 expression in patients with Merkel cell carcinoma and association with response to pembrolizumab[J]. J Immunother Cancer, 2018, 6(1): 99.
[3] Incorvaia L, Fanale D, Badalamenti G, et al. Programmed death ligand 1(PD-L1)as a predictive biomarker for pembrolizumab therapy in patients with advanced non-small-cell lung cancer(NSCLC)[J]. Adv Ther, 2019, 36(10): 2600-2617.
[4] Yang Q, Chen MJ, Gu JY, et al. Novel biomarkers of dynamic blood PD-L1 expression for immune checkpoint inhibitors in advanced non-small-cell lung cancer patients[J]. Front Immunol, 2021, 12: 665133.
[5] Shi YF, Lei YM, Liu L, et al. Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer[J]. Cancer Med, 2021, 10(7): 2216-2231.
[6] Lee SE, Kim YJ, Sung M, et al. Association with PD-L1 expression and clinicopathological features in 1 000 lung cancers: a large single-institution study of surgically resected lung cancers with a high prevalence of EGFR mutation[J]. Int J Mol Sci, 2019, 20(19): 4794.
[7] Lin AQ, Wei T, Meng H, et al. Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer(NSCLC)with EGFR mutations[J]. Mol Cancer, 2019, 18(1): 139.
[8] Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associatedwith low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis[J]. Clin Cancer Res, 2016, 22(18): 4585-4593.
[9] Lee J, Park CK, Yoon HK, et al. PD-L1 expression in ROS1-rearranged non-small cell lung cancer: a study using simultaneous genotypic screening of EGFR, ALK, and ROS1[J]. Thorac Cancer, 2019, 10(1): 103-110.
[10] 中国抗癌协会肿瘤病理专业委员会肺癌学组, 中国抗癌协会肺癌专业委员会, PD-L1检测共识专家组. 非小细胞肺癌PD-L1免疫组织化学检测规范中国专家共识[J]. 中国肺癌杂志, 2020, 23(9): 733-740.
[11] Cui PF, Li RX, Huang ZW, et al. Comparative effectiveness of pembrolizumabvs. nivolumab in patients with recurrent or advanced NSCLC[J]. Sci Rep, 2020, 10(1): 13160.
[12] Chen JX, Wang JH, Xu H. Comparison of atezolizumab, durvalumab, pembrolizumab, and nivolumab as first-line treatment in patients with extensive-stage small cell lung cancer: a systematic review and network meta-analysis[J]. Medicine(Baltimore), 2021, 100(15): e25180.
[13] Zhou CL, Tang JJ, Sun HH, et al. PD-L1 expression as poor prognostic factor in patients with non-squamous non-small cell lung cancer[J]. Oncotarget, 2017, 8(35): 58457-58468.
[14] Yu H, Batenchuk C, Badzio A, et al. PD-L1 expression by two complementary diagnostic assays and mRNA in situ hybridization in small cell lung cancer[J]. J Thorac Oncol, 2017, 12(1): 110-120.
[15] Carvajal-Hausdorf D, Altan M, Velcheti V, et al. Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung cancer(SCLC)[J]. J Immunother Cancer, 2019, 7(1): 65.
[16] Miao LL, Lu YY, Xu YJ, et al. PD-L1 and c-MET expression and survival in patients with small cell lung cancer[J]. Oncotarget, 2017, 8(33):53978-53988.
[17] Li X, Lian Z, Wang S, et al. Interactions between EGFR and PD-1/PD-L1 pathway: Implications for treatment of NSCLC[J]. Cancer Lett, 2018, 418: 1-9.
[18] Sato H, Okonogi N, Yoshimoto Y, et al. Radiotherapy and PD-L1 expression[J]. Gan To Kagaku Ryoho, 2019, 46(5): 845-849.
[19] 吴优倩. EGFR调控PD-L1稳定性及PD-1/PD-L1相互作用介导的肿瘤免疫反应的机制和功能研究[D]. 杭州: 浙江大学, 2019.
[20] Li CC, Liu J, Xie ZH, et al. PD-L1 expression with respect to driver mutations in non-small cell lung cancer in an Asian population: a large study of 1 370 cases in China[J]. Ther Adv Med Oncol, 2020, 12: 1758835920965840.
