不同检测策略在预测非小细胞肺癌的PD1/PD-L1抑制剂临床疗效中的应用
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摘要
近10年来,程序性死亡因子1(programmed death-1,PD-1)及其配体(programmed death ligand-1,PD-L1)的抑制剂在非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床治疗中取得了重大突破,有望改变晚期NSCLC的治疗方式。然而,PD-1/PD-L1抑制剂在对NSCLC的治疗中需要借助有效的生物标志物以寻找受益人群(约20%～40%)。目前,临床上主要的判断标准是PD-L1的表达水平。本文综述了近年来在NSCLC中,与预测PD-1/PD-L1抑制剂疗效的PD-L1表达相关的检测方法,包括免疫组化、基于DNA/RNA水平检测、可溶性PD-L1的检测、正电子发射断层显像(positron emission tomography,PET)技术、多重免疫组化技术、流式细胞术和液体活检技术等,着重探讨了不同检测策略在评价PD-L1表达上的最新进展及应用前景,从而推动其在NSCLC免疫治疗中的临床应用。
The last decade has witnessed great breakthroughs for the inhibitors of programmed death-1/programmed death ligand-1( PD-1/PD-L1) in non-small cell lung cancer( NSCLC), which was expected to improve the treatment for advanced NSCLC patients. The problem facing the clinical application of the inhibitors is finding potent biomarkers for outcome prediction,so far,the levels of PDL1 expression remain the main criteria. This review summarized the current progress on the detection of PD-L1 expression which was helpful in predicting clinical outcome of PD-1/PD-L1 inhibitors in advanced NSCLC,including immunohistochemistry( IHC),detection on DNA/RNA levels,detection of soluble PD-L1,positron emission tomography( PET),multiple IHC,flow cytometry,and liquid biopsy technique. Meanwhile,we discussed multiple strategies to optimize the evaluation of PD-L1 expression in this field to aid the clinical application of immunotherapy in NSCLC.
The last decade has witnessed great breakthroughs for the inhibitors of programmed death-1/programmed death ligand-1( PD-1/PD-L1) in non-small cell lung cancer( NSCLC), which was expected to improve the treatment for advanced NSCLC patients. The problem facing the clinical application of the inhibitors is finding potent biomarkers for outcome prediction,so far,the levels of PDL1 expression remain the main criteria. This review summarized the current progress on the detection of PD-L1 expression which was helpful in predicting clinical outcome of PD-1/PD-L1 inhibitors in advanced NSCLC,including immunohistochemistry( IHC),detection on DNA/RNA levels,detection of soluble PD-L1,positron emission tomography( PET),multiple IHC,flow cytometry,and liquid biopsy technique. Meanwhile,we discussed multiple strategies to optimize the evaluation of PD-L1 expression in this field to aid the clinical application of immunotherapy in NSCLC.
引文
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[2] Lu J,Ramirez RA. The role of checkpoint inhibition in nonsmall cell lung cancer[J]. Ochsner,J,2017,17(4):379-387
[3] Lin C,Jiang T. Liquid biopsy for monitoring EGFR-TKI drug resistance in patients with non-small-cell lung cancer[J]. Lab Med,2016,31(10):835-843
[4] Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor(WJTOG3405):an open label,randomised phase 3trial[J]. Lancet Oncol,2010,11(2):121-128
[5] Lategahn J,Keul M,Rauh D. Lessons to be learned:the molecular basis of kinase-targeted therapies and drug resistance in non-small cell lung cancer[J]. Angew Chem Int Ed Engl,2018,57(9):2307-2313
[6] Wang H,Yu X,Fan Y. Prospect and current situation of immune checkpoint inhibitors in first-line treatment in advanced nonsmall cell lung cancer patients[J]. Zhongguo Fei Ai Za Zhi,2017,20(6):427-432
[7] Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer,2012,12(4):252-264
[8] Lin C,Chen X,Liu J,et al. Advances of PD-1/PD-L1 signaling pathway in immune escape and treatment for non-small cell lung cancer[J]. Zhongguo Fei Ai Za Zhi,2014,17(10):734-740
[9] Ribas A. Releasing the Brakes on Cancer Immunotherapy[J]. N Engl J Med,2015,373(16):1490-1492
[10] Velcheti V,Schalper KA,Carvajal DE,et al. Programmed death ligand-1 expression in non-small cell lung cancer[J]. Lab Invest,2014,94(1):107-116
[11] Mc Laughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-smallcell lung cancer[J]. JAMA Oncol,2016,2(1):46-54
[12] Mao Y, Li W, Chen K, et al. B7-H1 and B7-H3 are independent predictors of poor prognosis in patients with nonsmall cell lung cancer[J]. Oncotarget,2015,6(5):3452-3461
[13] Zhang J,Gao J,Li Y,et al. Circulating PD-L1 in NSCLC patients and the correlation between the level of PD-L1 expression and the clinical characteristics[J]. Thorac Cancer,2015,6(4):534-538
[14] Sasaki H,Suzuki A,Shitara M,et al. PD-L1 gene expression in Japanese lung cancer patients[J]. Biomed Rep,2013,1(1):93-96
[15] Brody R,Zhang Y,Ballas M,et al. PD-L1 expression in advanced NSCLC:Insights into risk stratification and treatment selection from a systematic literature review[J]. Lung Cancer,2017,112:200-215
[16] Taube JM,Klein A,Brahmer JR,et al. Association of PD-1,PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy[J]. Clin Cancer Res,2014,20(19):5064-5074
[17] Rizvi NA,Hellmann MD,Snyder A,et al. Cancer immunology.Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer[J]. Science,2015,348(6230):124-128
[18] Heymann JJ,Bulman WA,Swinarski D,et al. PD-L1 expression in non-small cell lung carcinoma:Comparison among cytology,small biopsy, and surgical resection specimens[J]. Cancer Cytopathol,2017,125(12):896-907
[19] Stoy SP,Rosen L,Mueller J,et al. Programmed death-ligand 1testing of lung cancer cytology specimens obtained with bronchoscopy[J]. Cancer Cytopathol,2018,126(2):122-128
[20] Munari E,Zamboni G,Marconi M,et al. PD-L1 expression heterogeneity in non-small cell lung cancer:evaluation of small biopsies reliability[J]. Oncotarget,2017,8(52):90123-90131
[21] Parra ER,Villalobos P,Mino B,et al. Comparison of different antibody clones for immunohistochemistry detection of programmed cell death ligand 1(PD-L1)on non-small cell lung carcinoma[J]. Appl Immunohistochem Mol Morphol,2018,26(2):83-93
[22] Ilie M,Hofman V,Dietel M,et al. Assessment of the PD-L1status by immunohistochemistry:challenges and perspectives for therapeutic strategies in lung cancer patients[J]. Virchows Arch,2016,468(5):511-525
[23] Bingham V,Mc Ilreavey L,Greene C,et al. RNAscope in situ hybridization confirms mRNA integrity in formalin-fixed,paraffinembedded cancer tissue samples[J]. Oncotarget,2017,8(55):93392-93403
[24] Gafeer MM,Hosny Mohammed K,Ormenisan-Gherasim C,et al.Diagnostic Utility of PD-L1 expression in lung adenocarcinoma:immunohistochemistry and RNA in situ hybridization[J]. Appl Immunohistochem Mol Morphol,2018,26(8):e86-e90
[25] Shen-Orr SS, Gaujoux R. Computational deconvolution:extracting cell type-specific information from heterogeneous samples[J]. Curr Opin Immunol,2013,25(5):571-578
[26] Inoue Y,Yoshimura K,Mori K,et al. Clinical significance of PD-L1 and PD-L2 copy number gains in non-small-cell lung cancer[J]. Oncotarget,2016,7(22):32113-32128
[27] Goldmann T,Kugler C,Reinmuth N,et al. PD-L1 copy number gain in nonsmall-cell lung cancer defines a new subset of patients for anti PD-L1 therapy[J]. Ann Oncol,2016,27(1):206-207
[28] Budczies J,Bockmayr M,Denkert C,et al. Pan-cancer analysis of copy number changes in programmed death-ligand 1(PD-L1,CD274)-associations with gene expression,mutational load,and survival[J]. Genes Chromosomes Cancer,2016,55(8):626-639
[29] Li SD,Ma M,Li H,et al. Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3with therapeutic implications[J]. Genome Med, 2017, 9(1):89
[30] Zhu X,Lang J. Soluble PD-1 and PD-L1:predictive and prognostic significance in cancer[J]. Oncotarget,2017,8(57):97671-97682
[31] Zhou J,Mahoney KM,Giobbie-Hurder A,et al. Soluble PD-L1as a biomarker in malignant melanoma treated with checkpoint blockade[J]. Cancer Immunol Res,2017,5(6):480-492
[32] Truillet C,Oh HLJ,Yeo SP,et al. Imaging PD-L1 expression with immunoPET[J]. Bioconjug Chem,2018,29(1):96-103
[33] Kikuchi M, Clump DA, Srivastava RM, et al. Preclinical immunoPET/CT imaging using Zr-89-labeled anti-PD-L1monoclonal antibody for assessing radiation-induced PD-L1upregulation in head and neck cancer and melanoma[J].Oncoimmunology,2017,6(7):e1329071
[34] Lesniak WG,Chatterjee S,Gabrielson M,et al. PD-L1 detection in tumors using[(64)Cu]Atezolizumab with PET[J]. Bioconjug Chem,2016,27(9):2103-2110
[35] Chatterjee S,Lesniak WG,Nimmagadda S. Noninvasive imaging of immune checkpoint ligand PD-L1 in tumors and metastases for guiding immunotherapy[J]. Mol Imaging, 2017,16:1536012117718459
[36] Chatterjee S,Lesniak WG,Miller MS,et al. Rapid PD-L1detection in tumors with PET using a highly specific peptide[J].Biochem Biophys Res Commun,2017,483(1):258-263
[37] Takada K,Toyokawa G,Tagawa T,et al. Association between PD-L1 expression and metabolic activity on18F-FDG PET/CT in patients with small-sized lung cancer[J]. Anticancer Res,2017,37(12):7073-7082
[38] Takada K, Toyokawa G, Okamoto T, et al. Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on18F-fluorodeoxyglucose positron emission tomography/computed tomography[J]. Cancer Med, 2017, 6(11):2552-2561
[39] Kaira K,Higuchi T,Naruse I,et al. Metabolic activity by18FFDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC[J]. Eur J Nucl Med Mol Imaging,2018,45(1):56-66
[40] Feng Z,Puri S,Moudgil T,et al. Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma[J]. J Immunother Cancer,2015,3:47
[41] Stack EC, Wang C, Roman KA, et al. Multiplexed immunohistochemistry, imaging, and quantitation:a review,with an assessment of Tyramide signal amplification,multispectral imaging and multiplex analysis[J]. Methods,2014,70(1):46-58
[42] Giesen C,Wang HA,Schapiro D,et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry[J]. Nat Methods,2014,11(4):417-422
[43] Gorris MAJ,Halilovic A,Rabold K,et al. Eight-color multiplex immunohistochemistry for simultaneous detection of multiple immune checkpoint molecules within the tumor microenvironment[J]. J Immunol,2018,200(1):347-354
[44] Voong KR,Feliciano J,Becker D,et al. Beyond PD-L1 testingemerging biomarkers for immunotherapy in non-small cell lung cancer[J]. Ann Transl Med,2017,5(18):376
[45] Zheng H,Liu X,Zhang J,et al. Expression of PD-1 on CD4+T cells in peripheral blood associates with poor clinical outcome in non-small cell lung cancer[J]. Oncotarget,2016,7(35):56233-56240
[46] Meniawy TM,Lake RA,Mc Donnell AM,et al. PD-L1 on peripheral blood T lymphocytes is prognostic in patients with nonsmall cell lung cancer(NSCLC)treated with EGFR inhibitors[J]. Lung Cancer,2016,93:9-16
[47] Wang W,Yu D,Sarnaik AA,et al. Biomarkers on melanoma patient T cells associated with ipilimumab treatment[J]. J Transl Med,2012,10:146
[48] Coussens LM,Zitvogel L,Palucka AK. Neutralizing tumorpromoting chronic inflammation:a magic bullet?[J]. Science,2013,339(6117):286-291
[49] Coffelt SB,Kersten K,Doornebal CW,et al. IL-17-producingγδT cells and neutrophils conspire to promote breast cancer metastasis[J]. Nature,2015,522(7556):345-348
[50] Zelenay S, van der Veen AG, Bottcher JP, et al.Cyclooxygenase-dependent tumor growth through evasion of immunity[J]. Cell,2015,162(6):1257-1270
[51] Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity:a potential clue to unlock cancer immunotherapy[J]. Cancer J,2010,16(4):399-403
[52] Alix-Panabières C,Pantel K. Circulating tumor cells:liquid biopsy of cancer[J]. Clin Chem,2013,59(1):110-118
[53] Esposito A,Bardelli A,Criscitiello C,et al. Monitoring tumorderived cell-free DNA in patients with solid tumors:clinical perspectives and research opportunities[J]. Cancer Treat Rev,2014,40(5):648-655
[54] Giallombardo M, Chacártegui Borrás J,Castiglia M, et al.Exosomal miRNA analysis in non-small cell lung cancer(NSCLC)patients’plasma through qPCR:a feasible liquid biopsy tool[J]. J Vis Exp,2016,(111). doi:10. 3791/53900
[55] Lim SY,Lee JH,Welsh SJ,et al. Evaluation of two highthroughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients[J]. Biomark Res,2017,5:32
[56] Gallo M,De Luca A,Maiello MR,et al. Clinical utility of circulating tumor cells in patients with non-small-cell lung cancer[J]. Transl Lung Cancer Res,2017,6(4):486-498
[57] Nicolazzo C,Raimondi C,Mancini M,et al. Monitoring PD-L1positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab[J]. Sci Rep,2016,6:31726
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