PD-1/PD-L1抑制剂疗效预测的生物标志物

doi:10.3760/cma.j.issn.1673-422X.2018.12.011

摘要/Abstract

摘要： 随着肿瘤精准免疫治疗的发展，寻找预测程序性死亡受体1（PD1）/程序性死亡配体1（PDL1）响应能力的生物标志物成为该领域研究的一大热点。迄今已有多项预测指标如肿瘤组织PDL1的表达、肿瘤浸润淋巴细胞、肿瘤突变负荷、血清学标记甚至放射学指标在抗PD1/PDL1免疫治疗过程中显现了它们的价值，但每个预测指标都有其局限性。

关键词: 生物学标记, 预测, PD-1/PD-L1

Abstract: With the development of tumor precise immunotherapy, it is a hot topic to find biomarkers to predict the response ability of programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1). So far, many predictors, such as the PD-L1 expression in tumor tissue, tumorinfiltrating lymphocyte, tumor mutational burden, serum markers and radiographic markers, have shown predictive value in the process of antiPD-1/PD-L1 immunotherapy. But each predictor has its limitations.

Key words: Biological markers, Forecasting, PD-1/PD-L1

王阿香，高全立. PD-1/PD-L1抑制剂疗效预测的生物标志物[J]. 国际肿瘤学杂志, 2018, 45(12): 751-755.

Wang Axiang, Gao Quanli. Predictive biomarkers of efficacy to PD-1/PD-L1 inhibitors[J]. Journal of International Oncology, 2018, 45(12): 751-755.

参考文献

［1］ Blank C, Gajewski TF, Mackensen A. Interaction of PDL1 on tumor cells with PD1 on tumorspecific T cells as a mechanism of immune evasion: implications for tumor immunotherapy［J］. Cancer Immunol Immunother, 2005, 54(4): 307314. DOI: 10.1007/s002620040593x. ［2］ Liu B, Song Y, Liu D. Recent development in clinical applications of PD1 and PDL1 antibodies for cancer immunotherapy［J］. J Hematol Oncol, 2017, 10(1): 174. DOI: 10.1186/s1304501705419. ［3］ Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of antiPD1 antibody in cancer［J］. N Engl J Med, 2012, 366(26): 24432454. DOI: 10.1056/NEJMoa1200690. ［4］ Rizvi NA, Mazieres J, Planchard D, et al. Activity and safety of nivolumab, an antiPD1 immune checkpoint inhibitor, for patients with advanced, refractory squamous nonsmallcell lung cancer (CheckMate 063): a phase 2, singlearm trial［J］. Lancet Oncol, 2015, 16(3): 257265. DOI: 10.1016/S14702045(15)700549. ［5］ Brahmer JR, RodriguezAbreu D, Robinson AG, et al. Healthrelated qualityoflife results for pembrolizumab versus chemotherapy in advanced, PDL1positive NSCLC (KEYNOTE024): a multicentre, international, randomised, openlabel phase 3 trial［J］. Lancet Oncol, 2017, 18(12): 16001609. DOI: 10.1016/S14702045(17)306903. ［6］ Shen X, Zhao B. Efficacy of PD1 or PDL1 inhibitors and PDL1 expression status in cancer: metaanalysis［J］. BMJ, 2018, 362: k3529. DOI: 10.1136/bmj.k3529. ［7］ Mahoney KM, Sun H, Liao X, et al. PDL1 antibodies to its Cytoplasmic domain most clearly delineate cell membranesin immunohistochemical staining of tumor cells［J］. Cancer Immunol Res, 2015, 3(12): 13081315. DOI: 10.1158/23266066.CIR150116. ［8］ Hirsch FR, McElhinny A, Stanforth D, et al. PDL1 immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PDL1 IHC assay comparison project［J］. J Thorac Oncol, 2017, 12(2): 208222. DOI: 10.1016/j.jtho.2016.11.2228. ［9］ Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of nonsmallcell lung cancer［J］. N Engl J Med, 2015, 372(21): 20182028. DOI: 10.1056/NEJMoa1501824. ［10］ 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. DOI: 10.1158/10780432.CCR133271. ［11］ Ramakrishnan R, Assudani D, Nagaraj S, et al. Chemotherapy enhances tumor cell susceptibility to CTLmediated killing during cancer immunotherapy in mice［J］. J Clin Invest, 2010, 120(4): 11111124. DOI: 10.1172/JCI40269. ［12］ TwymanSaint VC, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate nonredundant immune mechanisms in cancer［J］. Nature, 2015, 520(7547): 373377. DOI: 10.1038/nature14292. ［13］ Heskamp S, Hobo W, MolkenboerKuenen JD, et al. Noninvasive imaging of tumor PDL1 expression using radiolabeled antiPDL1 antibodies［J］. Cancer Res, 2015, 75(14): 29282936. DOI: 10.1158/00085472.CAN143477. ［14］ Tumeh PC, Harview CL, Yearley JH, et al. PD1 blockade induces responses by inhibiting adaptive immune resistance［J］. Nature, 2014, 515(7528): 568571. DOI: 10.1038/nature13954. ［15］ Daud AI, Loo K, Pauli ML, et al. Tumor immune profiling predicts response to antiPD1 therapy in human melanoma［J］. J Clin Invest, 2016, 126(9): 34473452. DOI: 10.1172/JCI87324. ［16］ Chen DS, Mellman I. Elements of cancer immunity and the cancerimmune set point［J］. Nature, 2017, 541(7637): 321330. DOI: 10.1038/nature21349. ［17］ Teng MW, Ngiow SF, Ribas A, et al. Classifying cancers based on Tcell infiltration and PDL1［J］. Cancer Res, 2015, 75(11): 21392145. DOI: 10.1158/00085472.CAN150255. ［18］ Bhattacharyya NP, Skandalis A, Ganesh A, et al. Mutator phenotypes in human colorectal carcinoma cell lines［J］. Proc Natl Acad Sci U S A, 1994, 91(14): 63196323. ［19］ Le DT, Uram JN, Wang H, et al. PD1 blockade in tumors with mismatchrepair deficiency［J］. N Engl J Med, 2015, 372(26): 25092520. DOI: 10.1056/NEJMoa1500596. ［20］ Chen KH, Yuan CT, Tseng LH, et al. Case report: mismatch repair proficiency and microsatellite stability in gastric cancer may not predict programmed death1 blockade resistance［J］. J Hematol Oncol, 2016, 9: 29. DOI: 10.1186/s1304501602590. ［21］ Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden［J］. Genome Med, 2017, 9(1): 34. DOI: 10.1186/s1307301704242. ［22］ 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. DOI: 10.1126/science.aaa1348. ［23］ Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers［J］. Mol Cancer Ther, 2017, 16(11): 25982608. DOI: 10.1158/15357163.MCT170386. ［24］ Rizvi H, SanchezVega F, La K, et al. Molecular determinants of response to antiprogrammed cell death (PD)1 and antiprogrammed deathligand 1 (PDL1) blockade in patients with nonsmallcell lung cancer profiled with targeted nextgeneration sequencing［J］. J Clin Oncol, 2018, 36(7): 633641. DOI: 10.1200/JCO.2017.75.3384. ［25］ Mandal R, Chan TA. Personalized oncology meets immunology: the path toward precision immunotherapy［J］. Cancer Discov, 2016, 6(7): 703713. DOI: 10.1158/21598290.CD160146. ［26］ McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade［J］. Science, 2016, 351(6280): 14631469. DOI: 10.1126/science.aaf1490. ［27］ Domingo E, FreemanMills L, Rayner E, et al. Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer: a retrospective, pooled biomarker study［J］. Lancet Gastroenterol Hepatol, 2016, 1(3): 207216. DOI: 10.1016/S24681253(16)300140. ［28］ Briggs S, Tomlinson I. Germline and somatic polymerase epsilon and delta mutations define a new class of hypermutated colorectal and endometrial cancers［J］. J Pathol, 2013, 230(2): 148153. DOI: 10.1002/path.4185. ［29］ Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cellmediated immunotherapy［J］. Cancer Discov, 2016, 6(2): 202216. DOI: 10.1158/21598290.CD150283. ［30］ Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate［J］. Clin Cancer Res, 2017, 23(15): 42424250. DOI: 10.1158/10780432.CCR163133. ［31］ Weide B, Martens A, Hassel JC, et al. Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab［J］. Clin Cancer Res, 2016, 22(22): 54875496. DOI: 10.1158/10780432.CCR160127. ［32］ Sanmamed MF, PerezGracia JL, Schalper KA, et al. Changes in serum interleukin8 (IL8) levels reflect and predict response to antiPD1 treatment in melanoma and nonsmallcell lung cancer patients［J］. Ann Oncol, 2017, 28(8): 19881995. DOI: 10.1093/annonc/mdx190. ［33］ Kaira K, Higuchi T, Naruse I, et al. Metabolic activity by (18)FFDG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. DOI: 10.1007/s0025901738061. ［34］ Seith F, Forschner A, Schmidt H, et al. 18FFDGPET detects complete response to PD1therapy in melanoma patients two weeks after therapy start［J］. Eur J Nucl Med Mol Imaging, 2018, 45(1): 95101. DOI: 10.1007/s0025901738132.

[1]	刘玉兰, 井海燕, 孙静, 宋伟, 沙丹. 胃癌免疫治疗疗效预测及预后标志物的研究进展[J]. 国际肿瘤学杂志, 2024, 51(3): 175-180.
[2]	王雅倩, 杜逸玮, 王兴, 贾军梅. 小细胞肺癌免疫治疗预后预测指标研究进展[J]. 国际肿瘤学杂志, 2023, 50(3): 179-182.
[3]	范珊琳, 汪品秀, 孔飞, 周玉洁, 袁文臻. 胃癌新辅助化疗后肿瘤退缩分级预测因素的研究进展[J]. 国际肿瘤学杂志, 2023, 50(2): 112-116.
[4]	焦盼盼, 薛丽娟, 詹娟. 免疫检查点抑制剂相关不良反应的危险因素与预测因素[J]. 国际肿瘤学杂志, 2023, 50(12): 739-744.
[5]	陈郁, 许华, 刘海, 陈士新. 基于CT影像学特征的恶性肺纯磨玻璃结节患者病理分型预测模型构建[J]. 国际肿瘤学杂志, 2023, 50(11): 655-660.
[6]	丁心静, 丁江华. 皮肤免疫相关不良事件与PD-1/PD-L1抑制剂临床疗效相关性的研究进展[J]. 国际肿瘤学杂志, 2022, 49(4): 225-228.
[7]	李宁, 张玢琪. 免疫检查点抑制剂在子宫内膜癌中的应用[J]. 国际肿瘤学杂志, 2022, 49(2): 125-128.
[8]	朱一硕, 崔玉洁, 刘崎, 李军, 范月超. 脑胶质瘤患者术后早期复发危险因素分析及预测模型构建[J]. 国际肿瘤学杂志, 2022, 49(2): 79-83.
[9]	欧惠仪, 王越, 彭承宏. PD-L1与Treg在肿瘤免疫及治疗中的相关性[J]. 国际肿瘤学杂志, 2021, 48(6): 350-353.
[10]	张敏, 周丽娜, 徐姗姗, 陈骏. 肿瘤免疫治疗相关预测生物标志物研究进展[J]. 国际肿瘤学杂志, 2020, 47(8): 487-491.
[11]	徐阳涛, 陈彪, 何晓琴, 徐细明. 免疫治疗超进展的研究进展[J]. 国际肿瘤学杂志, 2020, 47(12): 737-740.
[12]	刘虹, 吴剑, 李宏江, 羊晓勤. 微小RNA在乳腺癌检测、治疗、耐药及预后中的研究进展[J]. 国际肿瘤学杂志, 2020, 47(12): 756-760.
[13]	张李卓, 钱杨洋, 郑国湾, 葛明华. PD-1/PD-L1在肿瘤中的机制研究及其在甲状腺癌中的诊治价值[J]. 国际肿瘤学杂志, 2020, 47(1): 39-42.
[14]	沈夏波, 王伟, 潘跃银. 血细胞参数在小细胞肺癌治疗中的预测作用[J]. 国际肿瘤学杂志, 2019, 46(8): 496-499.
[15]	白馨雅, 张金梦, 孙洋, 安永恒. 免疫检查点抑制剂在晚期非小细胞肺癌综合治疗中的应用[J]. 国际肿瘤学杂志, 2019, 46(8): 500-504.