亚洲人群非小细胞肺癌（non-small cell lung cancer，NSCLC）表皮生长因子受体（epidermal growth factor receptor，EGFR）突变发生率显著高于西方人群。近年来，以针对程序性死亡因子1（programmed cell death 1，PD-1）及程序性死亡因子配体1（programmed cell death ligand 1，PD-L1）抗体药物为代表的免疫治疗已成为晚期NSCLC临床治疗方案之一，开启肺癌免疫治疗新时代；然而既往研究报道EGFR突变型晚期NSCLC患者未能从免疫治疗单药中获益，不同EGFR突变型的患者对免疫治疗的响应也存在差异。最新临床研究ORIENT-31中期分析结果显示，免疫治疗联合化疗和抗血管生成药物显著改善了EGFR酪氨酸激酶抑制剂耐药的晚期NSCLC患者的无进展生存期，为此类EGFR突变型患者提供了新的临床治疗策略。EGFR突变型肿瘤组织微环境呈免疫抑制的状态，通过靶向肿瘤免疫抑制中发挥重要作用的靶点，促进EGFR突变型肿瘤对免疫治疗的响应，获得增效的新免疫联合治疗策略，可以丰富EGFR突变型晚期NSCLC患者在靶向治疗耐药后的临床治疗选择，进一步改善此类患者的生存预后。该文就EGFR突变型晚期NSCLC免疫治疗的最新临床研究进展、不同EGFR突变型免疫治疗效果差异、EGFR突变型NSCLC免疫联合治疗的增敏机制和潜在联合治疗方案进行综述。
关键词：非小细胞肺癌
;
表皮生长因子受体
;
免疫检查点抑制剂
;
突变型
Abstract
The incidence of epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) in Asians is significantly higher than that in Westerners. For the past few years, immune checkpoint inhibitors (ICIs) that target the programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) axis have become a part of the treatment paradigm for advanced NSCLC, opening a new era of immunotherapy for lung cancer. However, previous clinical trials reported that advanced NSCLC patients with EGFR mutation could not benefit from ICIs monotherapy. The immunotherapy outcomes of different EGFR mutant subtypes showed diverse. The interim results of the latest clinical trial ORIENT-31 showed that immunotherapy combined with chemotherapy and anti-angiogenesis significantly improved the progression-free survival of EGFR tyrosine kinase inhibitors (TKIs) resistant advanced NSCLC patients, providing a new therapeutic strategy for those EGFR mutant patients. The tumor microenvironment of EGFR-mutated NSCLC is immunosuppressed. Targeting the key immunomodulatory factors that play important roles in the immunosuppression may promote the response of EGFR-mutated tumors to immunotherapy and provide a new synergistic immune combination therapy strategy, which will enrich the clinical treatment options and improve the survival prognosis of EGFR-TKIs-resistant NSCLC patients. This article summarizes the latest clinical progression of immunotherapy in advanced NSCLC with EGFR mutation, the differences of immunotherapy efficacy among different EGFR mutation subtypes, the synergistic mechanism of combined immunotherapy and the potential molecular target combining with immunotherapy in EGFR-mutated NSCLC.
HUANG Huayan, XU-ZHANG Wendi, XIA Liliang, YU Yongfeng, LU Shun. Advances in immunotherapy of advanced non-small cell lung cancer with EGFR mutation. Journal of Shanghai Jiao Tong University (Medical Science)[J], 2023, 43(5): 611-618 doi:10.3969/j.issn.1674-8115.2023.05.012
以针对程序性死亡蛋白1（programmed cell death 1，PD-1）及程序性死亡受体配体1（programmed cell death ligand 1，PD-L1）抗体药物为代表的免疫检查点抑制剂（immune checkpoint inhibitor，ICI）显著改善了晚期NSCLC患者的生存［9］，开启了肺癌临床免疫治疗新时代。尽管临床前研究［10］表明，PD-1抗体通过增强效应T细胞功能和降低促癌细胞因子的水平改善了EGFR突变型肺腺癌患者的生存，但临床研究［11］表明，EGFR突变型NSCLC患者从免疫单药治疗获益有限。随着研究［12］的深入，发现不同EGFR突变类型对免疫治疗响应不同；并且EGFR-TKI耐药后患者可以从免疫治疗联合抗血管药物和化疗药物的治疗中获益［13-14］，这为EGFR突变患者在TKI治疗失败后提供了免疫治疗新方案。
与EGFR野生型患者相比，EGFR常见敏感突变（19del、L858R）型NSCLC患者接受免疫治疗的效果较差。一项多中心回顾性研究［12］结果显示：接受免疫单药治疗或双免疫联合治疗的80例EGFR 19del突变型晚期NSCLC患者与212例EGFR野生型患者相比，ORR较低（7% vs 22%），PFS和OS也显著缩短；而46例EGFR L858R突变型患者与EGFR野生型患者相比，PFS显著缩短，ORR（16% vs 22%）以及OS差异无统计学意义［12］。
EGFR 20ins突变型患者从一线免疫治疗中获益有限。美国一项研究［49］报道：129例EGFR 20ins突变型患者一线治疗的总ORR为18.6%，中位PFS和OS分别为5.2个月和17.0个月，其中免疫治疗单药组和免疫治疗联合化疗组ORR分别为9.1%和18.8%，中位PFS分别为3.1个月和4.5个月，中位OS分别为11.0个月和11.3个月，2种治疗对于这类患者效果均较差。另一项回顾性研究［50］报道，EGFR 20ins突变型晚期NSCLC患者经过一线治疗后，单纯化疗组和免疫治疗联合化疗组PFS无显著差异，免疫治疗联合化疗相比抗血管生成药物联合化疗，ORR相近（38.1% vs 40.0%），疾病控制率（disease control rate，DCR）更低（80.0% vs 96.8%），PFS无显著差异（6.5个月 vs 7.7个月）。对于此类EGFR突变亚型，仍需要更多研究探讨新的免疫联合治疗方案及效果。
HUANG Huayan participated in the topic selection and the design of the article, made contributions to the collection and analysis of relevant literature and wrote the first draft. XU-ZHANG Wendi, XIA Liliang and YU Yongfeng participated in the literature review and revision of the article. LU Shun proposed the topic selection and the design of the article, guided the writing of the paper and proposed suggestions for revision. All the authors have read the last version of paper and consented for submission.
利益冲突声明
所有作者声明不存在利益冲突。
COMPETING INTERESTS
All authors disclose no relevant conflict of interests.
SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
SHI Y K, AU J S K, THONGPRASERT S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER)[J]. J Thorac Oncol, 2014, 9(2): 154-162.
SORIA J C, OHE Y, VANSTEENKISTE J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer[J]. N Engl J Med, 2018, 378(2): 113-125.
ETTINGER D S, WOOD D E, AISNER D L, et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology[J]. J Natl Compr Canc Netw, 2022, 20(5): 497-530.
GARON E B, HELLMANN M D, RIZVI N A, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase Ⅰ KEYNOTE-001 study[J]. J Clin Oncol, 2019, 37(28): 2518-2527.
AKBAY E A, KOYAMA S, CARRETERO J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J]. Cancer Discov, 2013, 3(12): 1355-1363.
LEE C K, MAN J, LORD S, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer: a meta-analysis[J]. J Thorac Oncol, 2017, 12(2): 403-407.
HASTINGS K, YU H A, WEI W, et al. EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer[J]. Ann Oncol, 2019, 30(8): 1311-1320.
NOGAMI N, BARLESI F, SOCINSKI M A, et al. IMpower150 final exploratory analyses for atezolizumab plus bevacizumab and chemotherapy in key NSCLC patient subgroups with EGFR mutations or metastases in the liver or brain[J]. J Thorac Oncol, 2022, 17(2): 309-323.
LU S, WU L, JIAN H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial[J]. Lancet Oncol, 2022, 23(9): 1167-1179.
LISBERG A, CUMMINGS A, GOLDMAN J W, et al. A phase Ⅱ study of pembrolizumab in EGFR-mutant, PD-L1+, tyrosine kinase inhibitor naïve patients with advanced NSCLC[J]. J Thorac Oncol, 2018, 13(8): 1138-1145.
GARON E B, Wolf B, LISBERG A, et al. Prior TKI therapy in NSCLC EGFR mutant patients associates with lack of response to anti-PD-1 treatment[J]. J Thorac Oncol, 2015, 10(9 Suppl 2): S269.
GETTINGER S, RIZVI N A, CHOW L Q, et al. Nivolumab monotherapy for first-line treatment of advanced non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(25): 2980-2987.
PETERS S, GETTINGER S, JOHNSON M L, et al. Phase Ⅱ trial of atezolizumab as first-line or subsequent therapy for patients with programmed death-ligand 1-selected advanced non-small-cell lung cancer (BIRCH)[J]. J Clin Oncol, 2017, 35(24): 2781-2789.
RITTMEYER A, BARLESI F, WATERKAMP D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial[J]. Lancet, 2017, 389(10066): 255-265.
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.
GARASSINO M C, CHO B C, KIM J H, et al. Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study[J]. Lancet Oncol, 2018, 19(4): 521-536.
MAZIERES J, DRILON A, LUSQUE A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry[J]. Ann Oncol, 2019, 30(8): 1321-1328.
HAYASHI H, SUGAWARA S, FUKUDA Y, et al. A randomized phase Ⅱ study comparing nivolumab with carboplatin-pemetrexed for EGFR-mutated NSCLC with resistance to EGFR tyrosine kinase inhibitors (WJOG8515L)[J]. Clin Cancer Res, 2022, 28(5): 893-902.
AREDO J V, MAMBETSARIEV I, HELLYER J A, et al. Durvalumab for stage Ⅲ EGFR-mutated NSCLC after definitive chemoradiotherapy[J]. J Thorac Oncol, 2021, 16(6): 1030-1041.
HELLMANN M D, PAZ-ARES L, CARO R B, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer[J]. N Engl J Med, 2019, 381(21): 2020-2031.
HELLMANN M D, RIZVI N A, GOLDMAN J W, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study[J]. Lancet Oncol, 2017, 18(1): 31-41.
GUBENS M A, SEQUIST L V, STEVENSON J P, et al. Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer: KEYNOTE-021 cohorts D and H[J]. Lung Cancer, 2019, 130: 59-66.
SUGIYAMA E, TOGASHI Y, TAKEUCHI Y, et al. Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer[J]. Sci Immunol, 2020, 5(43): eaav3937.
YANG J C, GADGEEL S M, SEQUIST L V, et al. Pembrolizumab in combination with erlotinib or gefitinib as first-line therapy for advanced NSCLC with sensitizing EGFR mutation[J]. J Thorac Oncol, 2019, 14(3): 553-559.
CREELAN B C, YEH T C, KIM S W, et al. A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer[J]. Br J Cancer, 2021, 124(2): 383-390.
GETTINGER S, HELLMANN M D, CHOW L Q M, et al. Nivolumab plus erlotinib in patients with EGFR-mutant advanced NSCLC[J]. J Thorac Oncol, 2018, 13(9): 1363-1372.
OXNARD G R, YU H, et al. TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer[J]. Ann Oncol, 2020, 31(4): 507-516.
YANG J C H, SHEPHERD F A, KIM D W, et al. Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR TKI therapy: CAURAL brief report[J]. J Thorac Oncol, 2019, 14(5): 933-939.
SCHOENFELD A J, ARBOUR K C, RIZVI H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib[J]. Ann Oncol, 2019, 30(5): 839-844.
RIZVI N A, HELLMANN M D, BRAHMER J R, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer[J]. J Clin Oncol, 2016, 34(25): 2969-2979.
SHEN C A, CHAO H S, SHIAO T H, et al. Comparison of the outcome between immunotherapy alone or in combination with chemotherapy in EGFR-mutant non-small cell lung cancer[J]. Sci Rep, 2021, 11: 16122.
LIU S T, WU F Y, LI X F, et al. Patients with short PFS to EGFR-TKIs predicted better response to subsequent anti-PD-1/PD-L1 based immunotherapy in EGFR common mutation NSCLC[J]. Front Oncol, 2021, 11: 639947.
LU S, WU L, JIAN H, et al. Sintilimab with or without IBI305 plus chemotherapy in patients with EGFR mutated non-squamous non-small cell lung cancer (EGFRm nsqNSCLC) who progressed on EGFR tyrosine-kinase inhibitors (TKIs) therapy: second interim analysis of phase Ⅲ ORIENT-31 study[J]. Ann Oncol, 2022, 33: S1424.
LAM T C, TSANG K C, CHOI H C, et al. Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure[J]. Lung Cancer, 2021, 159: 18-26.
ROBICHAUX J P, LE X N, VIJAYAN R S K, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC[J]. Nature, 2021, 597(7878): 732-737.
CHEN Y, YANG Z Y, WANG Y N, et al. Pembrolizumab plus chemotherapy or anlotinib vs. pembrolizumab alone in patients with previously treated EGFR-mutant NSCLC[J]. Front Oncol, 2021, 11: 671228.
TIAN T, YU M, LI J, et al. Front-line ICI-based combination therapy post-TKI resistance may improve survival in NSCLC patients with EGFR mutation[J]. Front Oncol, 2021, 11: 739090.
CHEN Q, SHANG X L, LIU N, et al. Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors[J]. Front Immunol, 2022, 13: 931718.
YU H A, ARCILA M E, REKHTMAN N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers[J]. Clin Cancer Res, 2013, 19(8): 2240-2247.
YAMADA T, HIRAI S, KATAYAMA Y, et al. Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR-mutated non-small cell lung cancer[J]. Cancer Med, 2019, 8(4): 1521-1529.
YU X, LI J Q, YE L Y, et al. Real-world outcomes of chemo-antiangiogenesis versus chemo-immunotherapy combinations in EGFR-mutant advanced non-small cell lung cancer patients after failure of EGFR-TKI therapy[J]. Transl Lung Cancer Res, 2021, 10(9): 3782-3792.
HARATANI K, HAYASHI H, TANAKA T, et al. Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment[J]. Ann Oncol, 2017, 28(7): 1532-1539.
OU S H I, LIN H M, HONG J L, et al. Real-world response and outcomes in NSCLC patients with EGFR exon 20 insertion mutations[J]. J Clin Oncol, 2021, 39(15_suppl): 9098.
YANG G J, YANG Y N, LIU R Z, et al. First-line immunotherapy or angiogenesis inhibitor combined with chemotherapy for advanced non-small cell lung cancer with EGFR exon 20 insertions: real-world evidence from China[J]. Cancer Med, 2023, 12(1): 335-344.
HUNG M S, CHEN I C, LIN P Y, et al. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer[J]. Oncol Lett, 2016, 12(6): 4598-4604.
BORGSTRÖM P, HUGHES G K, HANSELL P, et al. Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and β2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels[J]. J Clin Invest, 1997, 99(9): 2246-2253.
HUANG Y H, YUAN J P, RIGHI E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy[J]. Proc Natl Acad Sci U S A, 2012, 109(43): 17561-17566.
VORON T, COLUSSI O, MARCHETEAU E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors[J]. J Exp Med, 2015, 212(2): 139-148.
STAGG J, DIVISEKERA U, DURET H, et al. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis[J]. Cancer Res, 2011, 71(8): 2892-2900.
LE X N, NEGRAO M V, REUBEN A, et al. Characterization of the immune landscape of EGFR-mutant NSCLC identifies CD73/adenosine pathway as a potential therapeutic target[J]. J Thorac Oncol, 2021, 16(4): 583-600.
TU E, MCGLINCHEY K, WANG J X, et al. Anti-PD-L1 and anti-CD73 combination therapy promotes T cell response to EGFR-mutated NSCLC[J]. JCI Insight, 2022, 7(3): e142843.
LIANG S Y, RISTICH V, ARASE H, et al. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6: STAT3 signaling pathway[J]. Proc Natl Acad Sci U S A, 2008, 105(24): 8357-8362.
GAO A Q, SUN Y P, PENG G Y. ILT4 functions as a potential checkpoint molecule for tumor immunotherapy[J]. Biochim Biophys Acta Rev Cancer, 2018, 1869(2): 278-285.
CHEN X Z, GAO A Q, ZHANG F, et al. ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation[J]. Theranostics, 2021, 11(7): 3392-3416.
... 以针对程序性死亡蛋白1（programmed cell death 1，PD-1）及程序性死亡受体配体1（programmed cell death ligand 1，PD-L1）抗体药物为代表的免疫检查点抑制剂（immune checkpoint inhibitor，ICI）显著改善了晚期NSCLC患者的生存［9］，开启了肺癌临床免疫治疗新时代.尽管临床前研究［10］表明，PD-1抗体通过增强效应T细胞功能和降低促癌细胞因子的水平改善了EGFR突变型肺腺癌患者的生存，但临床研究［11］表明，EGFR突变型NSCLC患者从免疫单药治疗获益有限.随着研究［12］的深入，发现不同EGFR突变类型对免疫治疗响应不同；并且EGFR-TKI耐药后患者可以从免疫治疗联合抗血管药物和化疗药物的治疗中获益［13-14］，这为EGFR突变患者在TKI治疗失败后提供了免疫治疗新方案. ...
... 与EGFR野生型患者相比，EGFR常见敏感突变（19del、L858R）型NSCLC患者接受免疫治疗的效果较差.一项多中心回顾性研究［12］结果显示：接受免疫单药治疗或双免疫联合治疗的80例EGFR 19del突变型晚期NSCLC患者与212例EGFR野生型患者相比，ORR较低（7% vs 22%），PFS和OS也显著缩短；而46例EGFR L858R突变型患者与EGFR野生型患者相比，PFS显著缩短，ORR（16% vs 22%）以及OS差异无统计学意义［12］. ...
... EGFR 20ins突变型患者从一线免疫治疗中获益有限.美国一项研究［49］报道：129例EGFR 20ins突变型患者一线治疗的总ORR为18.6%，中位PFS和OS分别为5.2个月和17.0个月，其中免疫治疗单药组和免疫治疗联合化疗组ORR分别为9.1%和18.8%，中位PFS分别为3.1个月和4.5个月，中位OS分别为11.0个月和11.3个月，2种治疗对于这类患者效果均较差.另一项回顾性研究［50］报道，EGFR 20ins突变型晚期NSCLC患者经过一线治疗后，单纯化疗组和免疫治疗联合化疗组PFS无显著差异，免疫治疗联合化疗相比抗血管生成药物联合化疗，ORR相近（38.1% vs 40.0%），疾病控制率（disease control rate，DCR）更低（80.0% vs 96.8%），PFS无显著差异（6.5个月 vs 7.7个月）.对于此类EGFR突变亚型，仍需要更多研究探讨新的免疫联合治疗方案及效果. ...
1
... EGFR 20ins突变型患者从一线免疫治疗中获益有限.美国一项研究［49］报道：129例EGFR 20ins突变型患者一线治疗的总ORR为18.6%，中位PFS和OS分别为5.2个月和17.0个月，其中免疫治疗单药组和免疫治疗联合化疗组ORR分别为9.1%和18.8%，中位PFS分别为3.1个月和4.5个月，中位OS分别为11.0个月和11.3个月，2种治疗对于这类患者效果均较差.另一项回顾性研究［50］报道，EGFR 20ins突变型晚期NSCLC患者经过一线治疗后，单纯化疗组和免疫治疗联合化疗组PFS无显著差异，免疫治疗联合化疗相比抗血管生成药物联合化疗，ORR相近（38.1% vs 40.0%），疾病控制率（disease control rate，DCR）更低（80.0% vs 96.8%），PFS无显著差异（6.5个月 vs 7.7个月）.对于此类EGFR突变亚型，仍需要更多研究探讨新的免疫联合治疗方案及效果. ...
2
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
... ［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... EGFR激活突变或过表达可导致EGFR信号通路的激活，诱导血管内皮生长因子（vascular endothelial growth factor，VEGF）表达上调［51］，从而驱动肿瘤生长.在EGFR突变的NSCLC组织中VEGF表达显著高于野生型对照［51］.VEGF可以通过抑制树突状细胞（dendritic cell，DC）成熟降低T细胞活化、减少T细胞肿瘤浸润和促进肿瘤免疫抑制的发生［52］.抗VEGF药物使肿瘤组织的脉管系统正常化，增加了免疫细胞向肿瘤组织的浸润，其具体机制包括内皮细胞的激活［53］，肿瘤内Ⅰ类主要组织相容性复合体（major histocompatibility complex class Ⅰ，MHC-Ⅰ）、辅助性T细胞1（helper T cell 1，Th1细胞）和效应T细胞标志物表达的增加以及趋化因子表达的增加，促进了CD8+ T细胞浸润增多［54］.抗血管生成药物还可以将肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）从免疫抑制性M2样表型极化为免疫刺激性M1样表型，促进CD4+ T细胞和CD8+ T细胞的肿瘤浸润［55］.肿瘤微环境中产生的VEGF可增强PD-1和其他免疫抑制性检查点的表达，促进CD8+ T细胞衰竭；靶向VEGF的抗血管生成药物可以逆转CD8+ T细胞的耗竭［56］.临床试验IMpower150［16］和ORIENT-31［17］也证明了免疫治疗联合抗血管生成药物及化疗，可以有效提高EGFR突变型患者免疫治疗的效果. ...
1
... CD73又称为胞外5′-核苷酸酶，是一种细胞表面酶；肿瘤细胞和调节性T细胞（regulatory T cell，Treg细胞）表达CD73，后者通过催化单磷酸腺苷转化为腺苷来抑制抗肿瘤免疫［57-58］.细胞外腺苷可损伤免疫细胞的功能，如T细胞、自然杀伤细胞（natural killer cell，NK细胞）、巨噬细胞和DC等；它还可促进Treg细胞和髓系来源抑制细胞（myeloid cell-derived suppressor cell，MDSC）的生成，从而促进肿瘤中免疫抑制微环境的形成［59］.临床前研究［60］表明，CD73-腺苷信号通路在EGFR突变型NSCLC中显著上调，且与免疫抑制性肿瘤微环境密切相关；在动物模型中，PD-L1抗体联合CD73抗体可以增强细胞毒性T细胞的活性，从而抑制肿瘤生长［61］.因此，阻断免疫检查点联合抑制CD73-腺苷信号通路可能是逆转EGFR突变型NSCLC中的免疫逃逸和免疫治疗抗性的潜在策略.目前CD73抗体联合PD-1/PD-L1抗体和CD73-PD-（L）1双抗的临床前及临床试验（NCT04262388、NCT03454451、NCT05431270、NCT05001347）正在进行中. ...
1
... CD73又称为胞外5′-核苷酸酶，是一种细胞表面酶；肿瘤细胞和调节性T细胞（regulatory T cell，Treg细胞）表达CD73，后者通过催化单磷酸腺苷转化为腺苷来抑制抗肿瘤免疫［57-58］.细胞外腺苷可损伤免疫细胞的功能，如T细胞、自然杀伤细胞（natural killer cell，NK细胞）、巨噬细胞和DC等；它还可促进Treg细胞和髓系来源抑制细胞（myeloid cell-derived suppressor cell，MDSC）的生成，从而促进肿瘤中免疫抑制微环境的形成［59］.临床前研究［60］表明，CD73-腺苷信号通路在EGFR突变型NSCLC中显著上调，且与免疫抑制性肿瘤微环境密切相关；在动物模型中，PD-L1抗体联合CD73抗体可以增强细胞毒性T细胞的活性，从而抑制肿瘤生长［61］.因此，阻断免疫检查点联合抑制CD73-腺苷信号通路可能是逆转EGFR突变型NSCLC中的免疫逃逸和免疫治疗抗性的潜在策略.目前CD73抗体联合PD-1/PD-L1抗体和CD73-PD-（L）1双抗的临床前及临床试验（NCT04262388、NCT03454451、NCT05431270、NCT05001347）正在进行中. ...
1
... CD73又称为胞外5′-核苷酸酶，是一种细胞表面酶；肿瘤细胞和调节性T细胞（regulatory T cell，Treg细胞）表达CD73，后者通过催化单磷酸腺苷转化为腺苷来抑制抗肿瘤免疫［57-58］.细胞外腺苷可损伤免疫细胞的功能，如T细胞、自然杀伤细胞（natural killer cell，NK细胞）、巨噬细胞和DC等；它还可促进Treg细胞和髓系来源抑制细胞（myeloid cell-derived suppressor cell，MDSC）的生成，从而促进肿瘤中免疫抑制微环境的形成［59］.临床前研究［60］表明，CD73-腺苷信号通路在EGFR突变型NSCLC中显著上调，且与免疫抑制性肿瘤微环境密切相关；在动物模型中，PD-L1抗体联合CD73抗体可以增强细胞毒性T细胞的活性，从而抑制肿瘤生长［61］.因此，阻断免疫检查点联合抑制CD73-腺苷信号通路可能是逆转EGFR突变型NSCLC中的免疫逃逸和免疫治疗抗性的潜在策略.目前CD73抗体联合PD-1/PD-L1抗体和CD73-PD-（L）1双抗的临床前及临床试验（NCT04262388、NCT03454451、NCT05431270、NCT05001347）正在进行中. ...
2
... CD73又称为胞外5′-核苷酸酶，是一种细胞表面酶；肿瘤细胞和调节性T细胞（regulatory T cell，Treg细胞）表达CD73，后者通过催化单磷酸腺苷转化为腺苷来抑制抗肿瘤免疫［57-58］.细胞外腺苷可损伤免疫细胞的功能，如T细胞、自然杀伤细胞（natural killer cell，NK细胞）、巨噬细胞和DC等；它还可促进Treg细胞和髓系来源抑制细胞（myeloid cell-derived suppressor cell，MDSC）的生成，从而促进肿瘤中免疫抑制微环境的形成［59］.临床前研究［60］表明，CD73-腺苷信号通路在EGFR突变型NSCLC中显著上调，且与免疫抑制性肿瘤微环境密切相关；在动物模型中，PD-L1抗体联合CD73抗体可以增强细胞毒性T细胞的活性，从而抑制肿瘤生长［61］.因此，阻断免疫检查点联合抑制CD73-腺苷信号通路可能是逆转EGFR突变型NSCLC中的免疫逃逸和免疫治疗抗性的潜在策略.目前CD73抗体联合PD-1/PD-L1抗体和CD73-PD-（L）1双抗的临床前及临床试验（NCT04262388、NCT03454451、NCT05431270、NCT05001347）正在进行中. ...
