Research progress of immune checkpoint inhibitors based biotherapeutics in epidermal growth factor receptor mutant of non-small cell lung cancer
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摘要: 对于表皮生长因子受体（EGFR）突变的患者，EGFR酪氨酸激酶抑制剂（EGFR-TKI）继发性耐药是不可避免的。免疫检查点抑制剂（ICIs）是目前癌症治疗的主要手段，包括抗程序性细胞死亡受体-1（PD-1）、程序性细胞死亡配体-1（PD-L1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的单克隆抗体，可显著改善非小细胞肺癌（NSCLC）患者的生存和生活质量。但携带EGFR突变的NSCLC患者对于ICIs反应较差。研究表明EGFR信号通路可能影响抗肿瘤免疫反应和肿瘤免疫微环境。本文就EGFR信号通路在肿瘤免疫微环境中对抗肿瘤免疫应答的影响、相关预后指标、EGFR突变患者的免疫治疗现状及目前的临床研究进行综述。
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关键词:
- 程序性细胞死亡受体-1 /
- 肿瘤微环境 /
- 免疫治疗 /
- 抗血管生成 /
- 表皮生长因子受体突变 /
- 非小细胞肺癌
Abstract: In patients with epidermal growth factor receptor (EGFR) mutation, secondary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI) is inevitable. Immune checkpoint inhibitors (ICIs) are currently the mainstay of cancer therapy, including monoclonal antibodies against programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which can significantly improve survival and quality of life in patients with non-small cell lung cancer (NSCLC). However, NSCLC patients with EGFR mutations have a poor response to ICIs. Studies have shown that EGFR signaling pathway may influence anti-tumor immune response and tumor immune microenvironment. This paper reviewed the effects of EGFR signaling pathway on tumor immune response in tumor immune microenvironment, related prognostic indicators, current status of immunotherapy for patients with EGFR mutation and current clinical studies. -
慢性阻塞性肺疾病(COPD)是临床常见的肺部疾病，其发病率与病死率在全球范围内逐渐递增[1-2]。COPD急性加重期(AECOPD)会引发Ⅱ型呼吸衰竭，与患者肺功能进一步下降及较高的病死率密切相关[3-4]。如何减轻AECOPD合并Ⅱ型呼吸衰竭患者的临床症状、改善其预后，是临床重点关注的问题。目前，在常规对症治疗的基础上联合应用无创机械通气仍是临床治疗AECOPD合并Ⅱ型呼吸衰竭的常见手段，而无创机械通气中不同吸入氧浓度对患者的临床疗效有所差异，有关吸入氧的适宜浓度仍存在争议[5]。血清高迁移率族蛋白B1(HMGB1)、白细胞介素-27(IL-27)在机体炎症反应的发生发展中发挥重要作用，其中HMGB1可在炎症条件下与晚期糖基化终产物受体、Toll样受体结合，启动多条信号通路，放大炎症效应; IL-27表达可诱导CD4+ T细胞增殖，促进多种炎症因子的合成分泌，加重炎症反应，其水平变化与COPD合并Ⅱ型呼吸衰竭患者的病情严重程度、预后密切相关[6-7]。本研究对比了无创机械通气中应用不同吸入氧浓度治疗对AECOPD合并Ⅱ型呼吸衰竭患者的血气指标、血清HMGB1、IL-27水平的影响，旨在为临床选择无创机械通气中合适的吸入氧浓度提供参考。
1. 资料与方法
1.1 一般资料
选取2020年1月—2022年12月于本院接受无创机械通气治疗的158例AECOPD合并Ⅱ型呼吸衰竭患者为研究对象，依据随机数字表法分为A组(无创机械通气中吸入氧浓度为45%, n=80)和B组(无创机械通气中吸入氧浓度为60%, n=78)。纳入标准: ①诊断符合AECOPD、Ⅱ型呼吸衰竭的诊断标准[8]者; ②均接受无创机械通气治疗者; ③患者性别不限，年龄≥18岁; ④患者知情同意。排除标准: ①既往存在家庭呼吸机使用史患者; ②合并其他类型肺部疾病患者; ③存在口咽部创伤或手术史患者; ④需立即气管插管治疗患者。治疗期间, A组1例患者死亡, 2例患者进入ICU, 1例患者未完成治疗周期脱落; B组2例患者进入ICU。最终纳入统计学分析患者152例, A组、B组各为76例。本研究经医院伦理委员会批准, 2组患者一般临床资料比较，差异无统计学意义(P>0.05)。见表 1。
表 1 2组患者一般临床资料比较(x±s)[n(%)]指标 A组(n=76) B组(n=76) t/χ2 P 性别 男 39(51.32) 34(44.74) 0.659 0.417 女 37(48.68) 42(55.26) 年龄/岁 57.81±6.29 56.92±5.17 0.953 0.342 体质量指数/(kg/m2) 23.47±1.29 23.86±1.61 1.648 0.101 基础疾病 糖尿病 23(30.26) 20(26.32) 0.292 0.589 高血压 26(34.21) 22(28.95) 0.487 0.485 吸烟史 37(48.68) 34(44.74) 0.238 0.626 COPD病程/年 3.62±1.37 3.27±1.26 1.2 方法
所有患者入院后均接受止咳化痰、抗炎、抗感染、纠正电解质紊乱等常规对症治疗。沙美特罗替卡松粉吸入剂(舒利迭; 规格: 每揿含沙美特罗25 μg和丙酸氟替卡松250 μg; 注册证号: H20140404; 法国Glaxo Wellcome Production公司), 1吸/次, 2次/d, 连续使用7 d。采用VPAPIII ST-A with QuickNav无创机械通气系统(瑞思迈医疗器械有限公司)行无创机械通气治疗，采用鼻导管或面罩连接呼吸机，通气模式为S/T模式，参数设置: 呼吸频率12~16次/min, 氧流量4~5 L/min, 初始治疗时吸气相正压(IPAP)10 cmH2O, 呼气末正压(EPAP)4 cmH2O, 待患者适应后，调整IPAP为10~20 cmH2O, EPAP为5~10 cmH2O; 1~3次/d, 每次通气3~4 h, 日通气时间≥8 h。A组患者吸入氧浓度为45%, B组患者吸入氧浓度为60%, 2组患者均连续治疗7 d。
1.3 观察指标
① 血气指标: 分别于治疗前及治疗后1、7 d取患者股动脉血5 mL, 采用全自动血气分析仪(cobas-b-123型，瑞士罗氏公司)检测患者动脉血氧分压[pa(O2)]、动脉血二氧化碳分压[pa(CO2)]和pH值。②血清HMGB1、IL-27水平检测: 分别于治疗前和治疗后1、7 d取患者空腹肘静脉血5 mL, 采用酶联免疫吸附法检测血清HMGB1、IL-27水平。③并发症: 记录患者治疗期间并发症的发生情况。
1.4 统计学分析
采用SPSS 23.0软件进行数据分析。计量资料以(x±s)表示，组间比较行t检验，组内不同时间点比较行重复测量方差分析; 计数资料以[n(%)]表示，行χ2检验或Fisher精确概率检验。检验水准α=0.05, P < 0.05表示差异有统计学意义。
2. 结果
2.1 2组患者治疗前后血气指标比较
治疗7 d后, A组pa(O2)、pH值水平高于B组, pa(CO2)水平低于B组，差异有统计学意义(P < 0.05)。见表 2。
表 2 2组患者治疗前后血气指标比较(x±s)指标 时点 A组(n=76) B组(n=76) pa(O2)/mmHg 治疗前 53.28±7.52 54.91±6.68 治疗1 d后 67.24±8.85 65.92±9.03 治疗7 d后 95.13±8.27* 82.49±9.35 pa(CO2)/mmHg 治疗前 68.27±8.54 69.63±7.48 治疗1 d后 53.48±6.65 55.29±7.23 治疗7 d后 39.79±5.28* 47.31±7.15 pH值 治疗前 7.23±0.11 7.20±0.15 治疗1 d后 7.36±0.12 7.33±0.09 治疗7 d后 7.39±0.05* 7.34±0.07 pa(O2): 动脉血氧分压; pa(CO2): 动脉血二氧化碳分压。与B组比较, * P < 0.05。 2.2 2组患者治疗前后血清HMGB1水平比较
治疗1、7 d后, A组血清HMGB1水平低于B组，差异有统计学意义(P < 0.05)。见表 3。
表 3 2组患者治疗前后血清HMGB1水平比较(x±s)μg/L 组别 高迁移率族蛋白B1 治疗前 治疗1 d后 治疗7 d后 A组(n=76) 4.08±1.13 3.25±0.79* 2.14±0.95* B组(n=76) 4.12±1.09 3.69±1.03 2.67±0.84 与B组比较, * P < 0.05。 2.3 2组患者治疗前后血清IL-27水平比较
治疗1、7 d后, A组血清IL-27水平低于B组，差异有统计学意义(P < 0.05)。见表 4。
表 4 2组患者治疗前后血清IL-27水平比较(x±s)ng/L 组别 白细胞介素-27 治疗前 治疗1 d后 治疗7 d后 A组(n=76) 187.24±39.26 125.31±20.81* 75.49±19.48* B组(n=76) 183.57±41.22 157.25±19.62 102.64±15.53 与B组比较, * P < 0.05。 2.4 2组并发症发生情况比较
治疗期间, 2组患者并发症总发生率比较，差异无统计学意义(P>0.05)。见表 5。
表 5 2组患者并发症发生情况比较[n(%)]组别 口咽干燥 鼻压伤 胃肠胀气 一过性低氧血症 合计 A组(n=76) 3(3.95) 2(2.63) 1(1.32) 0 6(7.89) B组(n=76) 1(1.32) 2(2.63) 1(1.32) 1(1.32) 5(6.58) 3. 讨论
AECOPD患者往往存在反复发作的低氧血症，会使肺小动脉痉挛，血流阻力增加，导致肺动脉血管重塑; 同时，随着肺功能的降低，患者呼吸肌收缩能力下降，易造成二氧化碳潴留，最终引发Ⅱ型呼吸衰竭，进一步增加患者的病死率。无创机械通气可通过减轻气流阻塞、增加动脉血氧饱和度来达到改善通气、缓解呼吸肌疲劳、减轻临床症状的效果。既往临床无创机械通气中多采用高浓度氧吸入治疗，以迅速改善低氧血症。但有研究[9]发现，过量吸入氧会增加呼吸中枢麻痹与继发性肺损伤的风险。无创机械通气中采用何种浓度的吸入氧治疗，尚需进一步研究。
本研究对比了无创机械通气中应用不同吸入氧浓度对AECOPD合并Ⅱ型呼吸衰竭患者血气指标及血清HMGB1、IL-27水平的影响。HMGB1是调节机体氧化应激及炎症反应的重要非组蛋白，具有启动并维持肺泡上皮细胞瀑布式炎症级联反应的作用，其水平变化与机体炎症反应的发生发展关系密切[10]。本研究发现，治疗1、7 d后, A组血清HMGB1水平显著低于B组，提示在无创机械通气中应用45%吸入氧浓度，可降低AECOPD合并Ⅱ型呼吸衰竭患者血清HMGB1水平，有利于患者机体炎症反应的控制。分析其原因可能是: 无创机械通气可改善患者气道通气状态，在降低气道阻力及患者呼吸肌做功的同时，提高肺泡换气功能，从而改善呼吸状态，减轻肺损伤; 但吸入氧浓度会对肺功能产生一定影响，浓度越高，肺部炎症反应越重，单核细胞合成分泌大量肿瘤坏死因子-α、白细胞介素-6等炎症因子，最终导致血清HMGB1水平升高[11]。
IL-27是由抗原呈递细胞分泌的细胞因子，可介导并激活多种信号级联反应，参与机体Th1细胞免疫应答，促进肿瘤坏死因子-α、干扰素-γ等细胞因子的合成与分泌[12]。一项有关血清IL-27水平与COPD合并Ⅱ型呼吸衰竭关系的分析研究[13]发现, COPD合并Ⅱ型呼吸衰竭患者的血清IL-27水平较单纯COPD患者、健康者显著升高，并与患者肺功能以及病情严重程度相关，认为IL-27参与气道炎症反应。本研究发现，治疗1、7 d后, A组血清IL-27水平显著低于B组，提示在无创机械通气中应用45%吸入氧浓度，可降低AECOPD合并Ⅱ型呼吸衰竭患者的血清IL-27水平，促进患者康复。高吸入氧浓度会诱导血管内皮生长因子信号通路改变，导致肺泡上皮细胞死亡，加重肺部炎症反应，使细胞炎症因子水平显著升高; 而高水平的细胞炎症因子会反过来促进IL-27的合成与分泌，使其水平显著升高[14]。
本研究结果显示，治疗7 d后, A组pa(O2)、pH值水平显著高于B组, pa(CO2)水平显著低于B组，提示采用45%吸入氧浓度的无创机械通气能更好地纠正AECOPD合并Ⅱ型呼吸衰竭患者的缺氧状态，改善其血气指标。COPD患者由于长期处于低氧状态，机体已具备低氧适应性，完全适应当前的低氧状态; 当吸入高浓度、高流量氧气时，可能会破坏机体的低氧适应性“稳态”，加重肺部炎症反应，不利于因呼吸衰竭造成的缺氧状态的改善[15]。研究[5]发现，与60%吸入氧浓度相比，在无创机械通气中应用45%吸入氧浓度能显著改善老年COPD合并呼吸衰竭患者的血氧指标和呼吸状况，并认为45%吸入氧浓度更符合患者机体状态，有利于相关组织正常生理功能的维护。本研究中，2组患者的并发症发生率无显著差异，进一步表明2种吸入氧浓度的安全性相当。但本研究为单中心临床试验，纳入样本量较少，后续研究拟扩大样本量，进一步多角度研究不同吸入氧浓度对AECOPD患者合并Ⅱ型呼吸衰竭的疗效，并对研究结果进行验证。
综上所述，与60%吸入氧浓度相比, AECOPD合并Ⅱ型呼吸衰竭患者接受吸入氧浓度为45%的无创机械通气治疗可获得更好的临床效果，患者血气指标改善效果更好，血清HMGB1、IL-27水平下降更显著，安全性较高。
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