程序性死亡受体1与其配体在T淋巴母细胞淋巴瘤/白血病中的表达及其临床意义

目的 研究程序性死亡受体1(PD-1)与程序性死亡配体1(PD-L1)在T淋巴母细胞淋巴瘤/白血病(T-LBL/ALL)中的表达情况,探讨两者的表达与患者临床病理特征及预后的关系.方法 应用免疫组织化学法(IHC)及实时荧光定量聚合酶链反应(qRT-PCR)对56例T-LBL/ALL(实验组)和20例淋巴结反应性增生(LH)(对照组)组织中PD-1与PD-L1表达水平进行检测.结果 IHC结果:PD-1在T-LBL/ALL肿瘤细胞不表达,在肿瘤浸润免疫细胞的阳性表达率为17.9 %(10/56),与对照组(90.0 %,18/20)相比,差异具有统计学意义(P=0.000).PD-L1蛋白在实验组和对照组的阳性率分别为37.5 %(21/56)和10.0 %(2/20),两组间比较差异具有统计学意义(P=0.044).qRT-PCR结果:T-LBL/ALL组中PD-L1 和PD-1 mRNA相对表达量均高于对照组(12.255比2.575;37.990比3.615),差异均有统计学意义(P<0.05).单因素分析:年龄、PD-L1蛋白和mRNA表达水平与预后有关(P<0.05).多因素Cox回归分析:PD-L1蛋白高表达及患者年龄≤25岁为独立的预后危险因素(P<0.05).结论 PD-1/PD-L1可能参与T-LBL/ALL的免疫逃逸,有望成为治疗T-LBL/ALL新的靶点.     

程序性死亡受体1/程序性死亡受体配体1免疫检查点抑制剂在乳腺癌免疫治疗中的应用前景

乳腺癌是女性病死率最高的恶性肿瘤,其发病率呈逐年增加趋势.程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)参与免疫检查点的调节,与乳腺癌的发生发展有着密切联系.PD-L1在不同组织类型的乳腺癌中表达不同,可作为诊断乳腺癌的生物标志物.PD-1/PD-L1免疫检查点是乳腺癌治疗中具有前景和挑战的靶点,其抑...     

PD-1/PD-L1抑制剂在晚期非小细胞肺癌中的治疗进展

程序性死亡受体1(programmed death 1,PD-1)抑制剂Pembrolizumab进入一线正式标志着免疫检查点抑制剂在晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗体系中占据了重要地位.临床试验结果证实PD-1/程序性死亡配体1(programmed death ligand 1,PD-L1)抑制剂在晚期NSCLC的一线、二线和多药耐药后治疗的疗效均要优于传统的化疗.一线使用Pembrolizumab联合化疗的客观有效率(objective response rate,ORR)最高可达80%;单药Pembrolizumab的无疾病进展时间(progression-free survival,PFS)接近1年(10.3个月),死亡风险比含铂双药化疗下降40%.单药Pembrolizumab、Nivolumab和Atezolizumab用于二线的疗效同样突出,总生存时间(overall survival,OS)可至1年左右.PD-L1的表达是PD-1/PD-L1抑制剂疗效的预测因子,在晚期NSCLC中阳性(≥1%)的比例约为60%左右,组织类型间差异不大,但是目前并无检测的金标准.     

PD-1/PD-L1在结直肠癌中的研究进展

程序性死亡受体-1 (programmed death 1,PD-1)与其配体(programmed death-ligand l,PD-L1)是目前免疫治疗中关注的焦点.PD-1与其配体PD-L1结合导致肿瘤微环境中T细胞衰竭及免疫逃逸,阻断PD-1与PD-L1结合是有效的治疗靶点.针对阻断PD-1/PD-L1通路的单克隆抗体通过美国FDA的审批己应用于临床,并已证实在恶性黑色素瘤、肺癌、膀胱癌、胃癌、霍奇金淋巴瘤、乳腺癌等多种恶性肿瘤的治疗中取得了显著效果,目前该疗法在结直肠癌(colorectal cancer,CRC)的治疗研究中也显示出了良好的疗效.本文对当前PD-1/PD-L1的分子结构、肿瘤免疫中的生物学功能和在结直肠癌微环境中的特点、临床病理分子特点、PD-1/PD-L1抑制剂治疗与耐药及预后方面的研究进展作一综述.     

PD-1/PD-L1信号通路在子宫内膜癌中的研究进展

子宫内膜癌作为女性生殖系统三大恶性肿瘤之一,早期治疗方法包括手术、放疗、化疗和内分泌治疗。晚期患者易发生转移或复发,预后较差。近年来靶向免疫检查点治疗成为肿瘤治疗的新热点,其中程序性死亡受体1/程序性死亡配体1(PD-1/PD-L1)在临床实验中显示出了较好的疗效和耐受性,本文将对PD-1/PD-L1信号通路相关的生物学基础,作用机制,其在子宫内膜癌及肿瘤微环境中表达及临床应用进行综述。     

PD-L2在血液系统肿瘤免疫治疗中的研究进展

随着程序性死亡受体1(programmed death receptor-1,PD-1)/程序性死亡受体配体1(programmed death-ligand 1,PD-L1)抑制剂在多种实体肿瘤临床治疗中取得广泛进展,血液系统肿瘤亦拉开了免疫疗法帷幕。然而,免疫检查点阻断疗法仍存在应答率低、药物耐药和副作用严重等挑战,需要进一步寻找新的免疫治疗靶点。B7家族中的程序性死亡受体配体2(programmed death-ligand 2,PD-L2)亦可以和PD-1结合,进而抑制免疫细胞功能。此外,PD-L2可以调控肿瘤免疫逃逸,在血液系统肿瘤中的治疗潜力仍有待研究。故本文对PD-L2的生物学特征、在血液系统肿瘤中的表达及在免疫治疗中的研究进展进行简要综述,为血液系统肿瘤通过PD-1/PD-L2通路治疗提供理论依据。     

非小细胞肺癌组织PD-L1的表达及其与临床因素的关系

目的:探索程序性死亡配体1 (programmed death-ligand 1,PD-L1)在中国非小细胞肺癌(non-small cell lung carcinoma,NSCLC)患者肿瘤组织中的表达水平及影响因素.方法:免疫组织化学法检测2008年4月至2014年8月天津医科大学肿瘤医院122例NSCLC初治患者肿瘤组织中PD-L1、PD-1和CD3+T细胞表达情况,采用x2和kruskal-wallis检验分析PD-L1表达在临床因素中分布差异性,用Person检验和Spearman检验分析PD-L1表达与EGFR基因型、CD3+T细胞数量及淋巴细胞PD-1表达的相关性,以及原发灶与淋巴结PD-L1表达相关性.结果:所有患者原发灶肿瘤细胞PD-L1表达百分比中位值1.5％(0～93.2％),PD-L1表达在TNM分期分布上有统计学差异(P =0.003),与TNM分期呈显著正相关(r=0.273,P=0.002),与性别、年龄、有无吸烟史、肿瘤最大径、病理类型、CEA水平分布无显著相关(P ＞0.05);PD-L1表达水平与CD3+T细胞数量、淋巴细胞PD-1表达水平无相关性,PD-L1表达阴性、低表达和高表达与表皮生长因子受体(epidermal growth factor receptor,EGFR)基因突变亦无显著相关(P ＞0.05);48例有淋巴结转移的NSCLC患者原发灶与相应转移淋巴结肿瘤细胞PD-L1表达水平无统计学相关性(P＞0.05).结论:NSCLC患者原发灶肿瘤细胞PD-L1表达在TNM分期分布上有差异,与CD3+T细胞数量、淋巴细胞PD-1表达水平、EGFR基因突变情况无相关性;原发灶与相应转移淋巴结之间肿瘤细胞PD-L1的表达亦没有相关性.     

PD-1/PD-L1抑制剂治疗淋巴瘤的研究进展

免疫检查点抑制剂已被批准用于多种难治性实体肿瘤的治疗,如恶性黑色素瘤、肺癌、胰腺癌、肾癌等。其在复发/难治性淋巴瘤的治疗方面也展现出广阔的应用前景。程序性死亡受体-1及其配体(PD-1/PD-L1)通路是免疫检查点抑制治疗(checkpoint blockade therapy,CBT)的关键性通路之一。肿瘤细胞可通过PD-1/PD-L1通路抑制T细胞活性,阻断免疫应答,从而实现免疫逃逸,最终促进肿瘤的发生、发展。新近研究发现PD-1/PD-L1通路在复发/难治性霍奇金淋巴瘤（Hodgkin lymphoma,HL）和部分非霍奇金淋巴瘤（non-Hodgkin lymphoma,NHL）中也发挥着重要作用。本文将简单介绍PD-1/PD-L1通路的生物学活性,总结针对该通路的免疫疗法在恶性淋巴瘤治疗中的研究进展。     

PD-1/PD-L1抑制剂治疗晚期非小细胞肺癌疗效预测的研究进展

程序性死亡受体-1(PD-1)抑制剂的使用为晚期非小细胞肺癌(NSCLC)的治疗掀开了前景广阔的新篇章.然而,目前尚缺乏有力的疗效预测指标来筛选使用PD-1抑制剂的患者,使得未经选择人群中的疗效相对较低,且存在出现免疫相关不良反应的风险.已有的临床试验多使用肿瘤细胞表面程序性死亡配体-1(PD-L1)的表达情况来预测疗效,然而预测结果不尽人意.近年来,随着对肿瘤免疫、肿瘤基因组学及肿瘤微环境的研究深入,肿瘤突变负荷、肺癌驱动基因、肿瘤浸润淋巴细胞等指标的疗效预测价值越来越受到重视.本文将对PD-1/PD-L1抑制剂治疗晚期NSCLC疗效预测的相关研究进行综述.     

非小细胞肺癌组织中PD-1/PD-L1的表达与EGFR突变的关系及其对预后的影响

目的:探讨非小细胞肺癌(non-small cell lung cancer, NSCLC)中程序性死亡受体1(programmed death receptor-1,PD-1)及程序性死亡受体配体1(programmed death receptor ligand-1,PD-L1)的表达和EGFR突变及其与预后的关系。方法:收集2013年01月至2015年12月由我院病理科经组织学诊断为非小细胞肺癌,并完成EGFR突变检测的150例患者的临床资料,应用免疫组织化学方法检测NSCLC组织中PD-1/PD-L1和CD8蛋白表达情况,分析其与临床病理参数及与EGFR突变的相关性,并对影响患者预后的多个临床病理因素进行分析。结果:非小细胞肺癌组织中PD-1/PD-L1和CD8的阳性表达率分别为34.7%(52/150)、50.4%(57/113)和59.2%(84/142)。其中PD-L1的表达与PD-1的表达(P=0.025,r_s=0.211)有关;PD-1的表达与术后病理分期(P=0.031,r_s=-0.177)及EGFR突变(P=0.001,...     

PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌疗效及安全性的Meta分析

目的：系统评价PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期非小细胞肺癌（non-small lung cancer,NSCLC）的疗效及安全性。方法：检索PubMed、Cochrane Library、EMbase、EBSCO循证医学数据库、中国生物医学文献数据库（Chinese Biomedical Literature Database,CBM）、中国知网（Chinese Journal Full-text Database,CNKI）、中文科技期刊全文数据库（VIP）中收录的PD-1/PD-L1 抑制剂联合化疗对比化疗一线治疗晚期NSCLC 的随机对照试验（randomized controlled trials,RCTs）,采用RevMan 5.2 软件进行Meta 分析。结果：纳入6 个临床RCTs 共3 238 例晚期NSCLC。Meta 分析结果显示,PD-1/PD-L1 抑制剂联合化疗与化疗相比可显著延长OS（HR=0.86,95%CI=0.79~0.94,P=0.0006）和PFS（HR=0.81,95%CI=0.78~0.84,P<0.00001）;1~5 级血小板计数减少、呕吐、腹泻、甲状腺功能减低或亢进、皮疹、肺炎、结肠炎、肝炎、味觉障碍,3~5 级肝炎的不良反应发生率较化疗组高,差异具有统计学意义（P<0.01 或P<0.05）。结论：PD-1/PD-L1 抑制剂联合化疗较单独化疗一线治疗晚期NSCLC可显著延长患者OS和PFS,但不良反应发生率较化疗高。     

KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated,PD-L1-positive,advanced NSCLC

KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m² every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.     

Immune checkpoint inhibitors in advanced non–small cell lung cancer

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first‐line and second‐line therapy settings for patients with advanced non–small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced‐stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue‐based and blood‐based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248‐61 . © 2017 American Cancer Society.     

Correlation between sex and efficacy of immune checkpoint inhibitors (PD‐1 and CTLA‐4 inhibitors)

Immune checkpoint inhibitors (ICIs) exert the antitumor efficacy depending on immune response, which is affected by sex difference, where both biological and sociological factors are involved. The role of sex in ICI trials has been overlooked. How sex correlates with ICI efficacy is incompletely understood. Clinical trials evaluating ICI versus other therapies in male and female patients were included. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and progression‐free survival (PFS) were used. Six thousand and ninety‐six patients from 11 trials were included. More improvement of OS was observed in males (HR, 0.62; 95% CI, 0.53–0.71; p < 0.001) treated with ICI versus controls than females (HR, 0.74; 95% CI, 0.65–0.84; p < 0.001). ICIs improved PFS more in males (HR, 0.57; 95% CI, 0.43–0.71; p < 0.001) than females (HR, 0.71; 95% CI, 0.52–0.91; p < 0.001). The sex difference had more effect on the overall survival in melanoma patients versus NSCLC patients. Overall survival of patients treated with CTLA‐4 inhibitor was more influenced by sex variable compared with PD‐1 inhibitors. A significant sex‐related efficacy difference was observed between female and male melanoma patients. Although male patients had longer OS and PFS than females when treated with ICIs versus controls, the difference was not significant. Sex difference should be more considered in future clinical trials, guidelines and clinical practice.     

Response rate as a potential surrogate for survival and efficacy in patients treated with novel immune checkpoint inhibitors: A meta-regression of randomised prospective studies

IntroductionTo assess the role of the tumour response rate (RR) after immune checkpoint inhibitors–based therapy as a potential surrogate end-point of progression-free survival (PFS) and overall survival (OS) in patients with solid tumours, we performed a trial-based meta-regression of randomised studies comparing different immune checkpoint inhibitors–based treatments.MethodsThe systematic literature search included the electronic databases and the proceedings of oncologic meetings. Treatment effects on PFS and OS were expressed as hazard ratios (HRs); treatment effects on RR were expressed as odds ratios (ORs). A weighted regression analysis was performed on log-transformed treatment effect estimates to test the association between treatment effects on the surrogate outcome and treatment effects on the clinical outcome.ResultsTwenty-four trials, for a total of 11,894 patients, were included in the analysis. Using the complete set of data, the regression of either the log(HR) for PFS or the log(HR) for OS on the log(OR) for RR demonstrated weak associations (R² = 0.47; 95% confidence interval [CI], 0.03–0.77; P = 0.001; and R² = 0.32; 95% CI, 0.02–0.76; P = 0.01, respectively). The pre-planned analyses stratifying trials according to different type of disease and different mechanism of action of immune checkpoint inhibitors showed a very weak association of the RR with the OS for non–small cell lung cancer indicated and a modest association of the RR with the PFS for cytotoxic T lymphocyte–associated antigen 4 checkpoint inhibitors.ConclusionThe results of the trial-based meta-regression analysis indicated a weak correlation between RR and OS, supporting future investigations to assess the surrogacy of RR in the patient treated with immune checkpoint inhibitors.     

A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer

BackgroundImmune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC.MethodsPatients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated.ResultsA total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 vs. 3.6 months, HR 0.47 (0.20–1.10), P=0.011] and PFS (median, 3.9 vs. 2.0 months, HR 0.58 (0.28–1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3–4 treatment-related adverse events (P=0.388).ConclusionsAnti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.     

非小细胞肺癌患者免疫检查点抑制剂相关性肺炎与免疫检查点抑制剂疗效相关性分析

目的：探讨免疫检查点抑制剂（ICI）治疗非小细胞肺癌（NSCLC）患者发生免疫检查点抑制剂相关性肺炎（CIP）的发生情况和免疫治疗疗效的关系，分析接受ICI 治疗的NSCLC患者的预后相关因素。方法：回顾性分析2020 年3月至2023 年3月在新疆医科大学附属肿瘤医院接受ICI 治疗145 例NSCLC患者的临床资料，将患者分为CIP 组和非CIP 组，随后将发生CIP 的患者分为轻度（1、2级）CIP 和重度（3、4级）CIP 两个亚组，通过Kaplan-Meier 法比较生存曲线，分析CIP 的发生及严重程度对于患者PFS 及OS的影响。通过单因素及多因素COX风险比例回归模型分析与PFS 和OS相关的预后因素。结果：145 例患者中有26例患者出现CIP，发生率为17.93％，重度CIP 发生率为3.45%。CIP 组患者PFS 明显长于非CIP 组患者（12.3 vs 7.6个月，P<0.05），CIP 组与非CIP 组的OS比较差异无统计学意义（16.2 vs 15.8个月，P>0.05)。亚组分析显示，轻度CIP 和重度CIP 相比，PFS（12.2vs 12.9 个月）及OS（16.1 vs 17.8 个月）均无统计学意义（均P>0.05）。多因素COX 回归分析显示，CIP[HR=0.55，95%CI（0.33,0.90），P=0.02]、免疫疗程>6 个[HR=0.51 ，95%CI（0.31, 0.85），P=0.01]是影响患者PFS 的有利预后因素，免疫疗程>6 个[HR=0.4，95%CI（0.18, 0.88），P=0.02]是影响OS的有利预后因素。结论：CIP 的发生率为17.93％，CIP 的发生与PFS 的延长密切相关。免疫疗程>6个是影响NSCLC患者PFS、OS的有利预后因素。     

Checkpoint Inhibitors in Metastatic EGFR-Mutated Non–Small Cell Lung Cancer—A Meta-Analysis

IntroductionWe performed a meta-analysis to assess the role of immune checkpoint inhibitors as second-line therapy in EGFR-mutant advanced NSCLC.MethodsRandomized trials comparing immune checkpoint inhibitors against chemotherapy were identified. We retrieved the hazard ratio (HR) and 95% confidence interval (CI) for overall survival (OS) of the intention-to-treat population and EGFR mutation–defined subgroups. We used the fixed-effects inverse variance–weighted method to pool estimates of treatment efficacy. Statistical tests were two sided.ResultsIn the three included studies that compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) against docetaxel (n = 776), immune checkpoint inhibitors significantly prolonged OS over that with docetaxel overall (n = 1903, HR = 0.68, 95% CI: 0.61–0.77, p < 0.0001) and in the EGFR wild-type subgroup (n = 1362, HR = 0.66, 95% CI: 0.58–0.76, p < 0.0001) but not in the EGFR-mutant subgroup (n = 186, HR = 1.05, 95% CI: 0.70–1.55, p < 0.81; treatment-mutation interaction p = 0.03).ConclusionIn EGFR-mutant advanced NSCLC, immune checkpoint inhibitors do not improve OS over that with docetaxel. Mechanisms of acquired resistance to first-line tyrosine kinase inhibitor therapy should be elucidated to guide selection of second-line treatment for these patients.     

Improved treatment outcome of pembrolizumab in patients with nonsmall cell lung cancer and chronic obstructive pulmonary disease

Emerging immune profiling data suggest a higher sensitivity to immune checkpoint inhibitors (ICIs) in nonsmall cell lung cancer (NSCLC) patients with chronic obstructive pulmonary disease (COPD), compared to those without COPD. This study aimed to investigate the clinical impact of COPD on the treatment response to ICIs in a large number of patients with NSCLC. In total, 133 patients with spirometry test results were retrospectively identified among those who received palliative pembrolizumab for NSCLC. COPD was defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity <0.7. Overall survival (OS), progression-free survival (PFS), and objective response rate were analyzed according to the presence of COPD. Spirometry-based COPD was present in 59 (44%) patients. Patients with COPD had better OS (hazard ratio [HR] for death, 0.45; 95% confidence interval [CI], 0.26–0.78) and PFS (HR for disease progression or death, 0.50; 95% CI, 0.31–0.79) than those without COPD. These associations persisted after adjusting for potential confounders including smoking history. The response rate was also higher in patients with COPD than in those without COPD (38.2% vs. 20.5%, p = 0.028). Spirometry-defined COPD was associated with a significantly longer OS and PFS in patients with NSCLC treated with palliative pembrolizumab. Identifying coexisting COPD could predict favorable treatment outcomes in patients with NSCLC treated with pembrolizumab.     

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

IntroductionAccording to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)–negative and tumor-infiltrating lymphocyte (TIL)–negative (type I); (2) PD-L1–positive and TIL-positive (type II); (3) PD-L1–negative and TIL-positive (type III); and (4) PD-L1–positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC.MethodsOn the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy.ResultsPD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06–0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13–0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes.ConclusionsOnly patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.