胃肠胰神经内分泌肿瘤的免疫治疗研究进展

doi:10.11904/j.issn.1002-3070.2021.02.010

摘要/Abstract

摘要： 晚期胃肠胰神经内分泌肿瘤(Gastroenteropancreatic neuroendocrine neoplasms,GEP-NENs)的治疗药物有限,且疗效不佳。免疫治疗作为一种有前景的治疗方式,近年来在GEP-NENs中进行了初步应用探索。目前已有研究结果显示免疫检查点抑制剂在GEP-NENs中有良好的抗肿瘤活性和安全性。程序性死亡配体(PD-L1)在不同GEP-NENs的原发部位中表达有所差异,且与肿瘤分化程度呈负相关。PD-L1表达程度及免疫细胞浸润对GEP-NENs患者预后的影响仍有争议。能够预测免疫治疗获益的生物标志物尚未确定。本文就GEP-NENs的免疫治疗研究进展做一综述。

关键词: 胃肠胰神经内分泌肿瘤, 生物标志物, 免疫治疗, 免疫检查点抑制剂

Abstract: Advanced gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have limited therapeutic drugs and poor efficacy.As a promising treatment method,immunotherapy has been initially explored in GEP-NENs in recent years.Current research results show that immune checkpoint inhibitors have good anti-tumor activity and safety in GEP-NENs.The expression of PD-L1 in the primary site of different GEP-NENs is different,and it is negatively correlated with the degree of differentiation.The effect of PD-L1 expression and immune cell infiltration on the prognosis of GEP-NENs patients is still controversial.The biomarkers that can predict the benefits of immunotherapy have not yet been determined.This article reviews the research progress of immunotherapy for GEP-NENs.

Key words: Gastroenteropancreatic neuroendocrine tumors;Biomarkers;Immunotherapy;Immune checkpoint inhibitors

中图分类号:

R730.51

王萌萌, 连洁, 李恒震, 张艳桥. 胃肠胰神经内分泌肿瘤的免疫治疗研究进展[J]. 实用肿瘤学杂志, 2021, 35(2): 154-159.

WANG Mengmeng, LIAN Jie, LI Hengzhen, ZHANG Yanqiao. Research progress in immunotherapy of gastrointestinal pancreatic neuroendocrine tumors[J]. Journal of Practical Oncology, 2021, 35(2): 154-159.

0
/ / 推荐

导出引用管理器 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

链接本文: http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/10.11904/j.issn.1002-3070.2021.02.010

http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/Y2021/V35/I2/154

参考文献

1 Dasari A,Shen C,Halperin D,et al.Trends in the incidence,prevalence,and survival outcomes inpatients with neuroendocrine tumors in the United States[J].JAMA Oncol,2017,3(10):1335-1342.
2 Nagtegaal ID,Odze RD,Klimstra D,et al.The 2019 WHO classification of tumours of the digestive system[J].Histopathology,2020,76(2):182-188.
3 Merola E,Panzuto F,Delle Fave G.Antiproliferative effect of somatostatin analogs in advanced gastro-entero-pancreatic neuroendocrine tumors:a systematic review and meta-analysis[J].Oncotarget,2017,8(28):46624-46634.
4 Yao JC,Pavel M,Lombard-Bohas C,et al.Everolimus for the treatment of advanced pancreatic neuroendocrine tumors:overall survival and circulating biomarkers from the randomized,phase III RADIANT-3 study[J].J Clin Oncol,2016,34(32):3906-3913.
5 Zhang J,Liu Q,Singh A,et al.Prognostic value of(18)F-FDG PET/CT in a large cohort of 495 patients with advanced metastatic neuroendocrine neoplasms(NEN)treated with peptide receptor radionuclide therapy(PRRT)[J].J Nucl Med,2020,61(11):1560-1569.
6 Angelousi A,Kamp K,Kaltsatou M,et al.Sequential everolimus and sunitinib treatment in pancreatic metastatic well-differentiated neuroendocrine tumours resistant to prior treatments[J].Neuroendocrinology,2017,105(4):394-402.
7 Angelousi A,Kaltsas G,Koumarianou A,et al.Chemotherapy in NETs:when and how[J].Rev Endocr Metab Disord,2017,18(4):485-497.
8 Myint ZW,Goel G.Role of modern immunotherapy in gastrointestinal malignancies:a review of current clinical progress[J].J Hematol Oncol,2017,10(1):86.
9 Keir ME,Butte MJ,Freeman GJ,et al.PD-1 and its ligands in tolerance and immunity[J].Annu Rev Immunol,2008,26,677-704.
10 Su MY,Fisher DE.Immunotherapy in the precision medicine era:melanoma and beyond[J].PLoS Med,2016,13(12):e1002196.
11 Butte MJ,Keir ME,Phamduy TB,et al.Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses[J].Immunity,2007,27(1):111-122.
12 Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
13 Patel SP,Kurzrock R.PD-L1 Expression as a predictive biomarker in cancer immunotherapy[J].Mol Cancer Ther,2015,14(4):847-856.
14 Aguiar PN,Jr Santoro IL,Tadokoro H,et al.The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer:a network meta-analysis[J].Immunotherapy,2016,8(4):479-488.
15 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.
16 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.
17 Colle R,Cohen R,Cochereau D,et al.Immunotherapy and patients treated for cancer with microsatellite instability[J].Bull Cancer,2017,104(1):42-51.
18 Lu M,Zhang P,Zhang Y,et al.Efficacy,safety,and biomarkers of toripalimab in patients with recurrent or metastatic neuroendocrine neoplasms:a multiple-center phase ib trial[J].Clin Cancer Res,2020,26(10):2337-2345.
19 Ott PA,Bang YJ,Piha-Paul SA,et al.T-cell-inflamed gene-expression profile,programmed death ligand 1 expression,and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers:KEYNOTE-028[J].J Clin Oncol,2019,37(4):318-327.
20 Vijayvergia N,Dasari A,Deng M,et al.Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms:joint analysis of two prospective,non-randomised trials[J].Br J Cancer,2020,122(9):1309-1314.
21 Strosberg J,Mizuno N,Doi T,et al.Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors:results from the phase II KEYNOTE-158 study[J].Clin Cancer Res,2020,26(9):2124-2130.
22 Patel SP,Othus M,Chae YK,et al.A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors(DART SWOG 1609)in patients with nonpancreatic neuroendocrine tumors[J].Clin Cancer Res,2020,26(10):2290-2296.
23 Horn L,Mansfield AS,Szczesna A,et al.First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J].N Engl J Med,2018,379(23):2220-2229.
24 Boku N,Ryu MH,Kato K,et al.Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated,unresectable,advanced,or recurrent gastric/gastroesophageal junction cancer:interim results of a randomized,phase II trial(ATTRACTION-4)[J].Ann Oncol,2019,30(2):250-258.
25 Burtness B,Harrington KJ,Greil R,et al.Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck(KEYNOTE-048):a randomised,open-label,phase 3 study[J].Lancet,2019,394(10212):1915-1928.
26 Ono K,Shiozawa E,Ohike N,et al.Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms:a retrospective study of 136 patients[J].Oncol Lett,2018,15(2):2123-2130.
27 Ferrata M,Schad A,Zimmer S,et al.PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic(GEP)and Non-GEP neuroendocrine neoplasms with high proliferative activity[J].Front Oncol,2019,9:343.
28 Sampedro-Nunez M,Serrano-Somavilla A,Adrados M,et al.Analysis of expression of the PD-1/PD-L1 immune checkpoint system and its prognostic impact in gastroenteropancreatic neuroendocrine tumors[J].Sci Rep,2018,8(1):17812.
29 Kim ST,Ha SY,Lee S,et al.The impact of PD-L1 expression in patients with metastatic GEP-NETs[J].J Cancer,2016,7(5):484-489.
30 Roberts JA,Gonzalez RS,Das S,et al.Expression of PD-1 and PD-L1 in poorly differentiated neuroendocrine carcinomas of the digestive system:a potential target for anti-PD-1/PD-L1 therapy[J].Hum Pathol,2017,70:49-54.
31 Xing J,Ying H,Li J,et al.Immune checkpoint markers in neuroendocrine carcinoma of the digestive system[J].Front Oncol,2020,10:132.
32 Cives M,Strosberg J,Al Diffalha S,et al.Analysis of the immune landscape of small bowel neuroendocrine tumors[J].Endocr Relat Cancer,2019,26(1):119-130.
33 Sahnane N,Furlan D,Monti M,et al.Microsatellite unstable gastrointestinal neuroendocrine carcinomas:a new clinicopathologic entity[J].Endocr Relat Cancer,2015,22(1):35-45.
34 Mei M,Deng D,Liu TH,et al.Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas[J].J Clin Endocrinol Metab,2009,94(9):3448-3457.
35 Arnason T,Sapp HL,Rayson D,et al.Loss of expression of DNA mismatch repair proteins is rare in pancreatic and small intestinal neuroendocrine tumors[J].Arch Pathol Lab Med,2011,135(12):1539-1544.
36 Kidd M,Eick G,Shapiro MD,et al.Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors[J].Cancer,2005,103(2):229-236.
37 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.
38 Yang MW,Fu XL,Jiang YS,et al.Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas[J].World J Gastroenterol,2019,25(14):1684-1696.
39 Bosch F,Bruwer K,Altendorf-Hofmann A,et al.Immune checkpoint markers in gastroenteropancreatic neuroendocrine neoplasia[J].Endocr Relat Cancer,2019,26(3):293-301.
40 Cai L,Michelakos T,Deshpande V,et al.Role of tumor-associated macrophages in the clinical course of pancreatic neuroendocrine tumors(PanNETs)[J].Clin Cancer Res,2019,25(8):2644-2655.
41 Melero I,Berman DM,Aznar MA,et al.Evolving synergistic combinations of targeted immunotherapies to combat cancer[J].Nat Rev Cancer,2015,15(8):457-472.

[1]	王明明, 陈晓品. 抗PD-1/PD-L1和CTLA-4免疫治疗在头颈鳞癌中的研究进展[J]. 实用肿瘤学杂志, 2021, 35(2): 179-183.
[2]	李瑞阳,方琳(综述),张艳桥(审校). 食管癌免疫治疗研究进展[J]. 实用肿瘤学杂志, 2021, 35(1): 41-45.
[3]	刘学静(综述),徐燕颖(审校). B7-H6在恶性肿瘤中的研究进展[J]. 实用肿瘤学杂志, 2021, 35(1): 46-49.
[4]	张璐,陆静钰(综述),陆海军(审校). 头颈部鳞癌相关生物标志物与免疫治疗预后的关系[J]. 实用肿瘤学杂志, 2021, 35(1): 55-58.
[5]	冯羽昕(综述),朱春荣(审校). lncRNA-HEIH在肿瘤中的研究进展[J]. 实用肿瘤学杂志, 2021, 35(1): 87-90.
[6]	石琳娜, 隋红. 原发性肝癌免疫检查点抑制剂治疗的进展与挑战[J]. 实用肿瘤学杂志, 2020, 34(6): 560-564.
[7]	范晓娜, 王丹, 黎清炜, 李志伟. 胰腺癌术后辅助药物治疗的研究进展[J]. 实用肿瘤学杂志, 2020, 34(3): 249-253.
[8]	侯建英, 朱巍. 免疫抑制剂PD-1/PD-L1治疗卵巢癌的研究进展[J]. 实用肿瘤学杂志, 2020, 34(3): 266-270.
[9]	刘超, 郑桐森. 新冠肺炎时期肿瘤内科工作的总结和反思[J]. 实用肿瘤学杂志, 2020, 34(2): 100-102.
[10]	曹涤非, 黄国庆, 薛佳莹, 吴琼, 王雷, 李瑶. CA153在乳腺癌免疫治疗中的作用[J]. 实用肿瘤学杂志, 2019, 33(6): 566-569.
[11]	赵金璐, 李国东刘明. 长链非编码RNA CCAT1与消化系统恶性肿瘤关系的研究进展[J]. 实用肿瘤学杂志, 2019, 33(4): 367-370.
[12]	姚洋张艳桥. 胃癌免疫检查点抑制剂作用机制及最新研究进展[J]. 实用肿瘤学杂志, 2019, 33(4): 371-375.
[13]	孙祖刚, 王哲, 陈怀安, 刘硕, 苗文隆. 诱发膀胱癌的常见慢性炎症因素及其免疫治疗的研究进展[J]. 实用肿瘤学杂志, 2018, 32(4): 357-361.
[14]	张婷, 贾迪(综述), 杨丹(审校). 骨肉瘤的生物学治疗进展[J]. 实用肿瘤学杂志, 2018, 32(3): 254-257.
[15]	苗素平, 郭二亮, 裴荣, 姜寰宇, 苗素生. miRNA调节免疫检查点在肿瘤治疗中的研究进展[J]. 实用肿瘤学杂志, 2018, 32(1): 57-62.