PD-1抑制剂治疗肝细胞癌疗效相关生物标志物的研究现状

doi:10.11904/j.issn.1002-3070.2022.04.016

摘要/Abstract

摘要： 近年来免疫治疗在肝细胞癌辅助治疗领域取得了初步成果,而程序性死亡受体1(Programmed cell death-1,PD-1)抑制剂是目前的研究热点,然而其总反应率仍不尽如人意,因此目前急需寻找合适的生物标志物,来预测PD-1抑制剂治疗肝细胞癌患者的疗效,本文就PD-1抑制剂治疗肝细胞癌的相关生物标志物的研究进展进行综述。

关键词: PD-1抑制剂, 肝细胞癌, 生物标志物

Abstract: In recent years,immunotherapy has achieved preliminary results in the field of adjuvant therapy for liver cancer.Programmed cell death-1(PD-1)inhibitors are the current research hotspot,but the overall response rate is still not high.As expected,there is an urgent need to find suitable biomarkers to predict the efficacy of PD-1 inhibitors in the treatment for liver cancer patients.This article reviews the research progress of PD-1 inhibitor therapy related biomarkers for hepatocellular carcinoma.

Key words: PD-1 inhibitor, Hepatocellular carcinoma, Biomarkers

中图分类号:

R735.7

刘佳, 杨道坤, 王燕平, 陈宝鑫, 王新伟, 申娇. PD-1抑制剂治疗肝细胞癌疗效相关生物标志物的研究现状[J]. 实用肿瘤学杂志, 2022, 36(4): 374-380.

LIU Jia, YANG Daokun, WANG Yanping, CHEN Baoxin, WANG Xinwei, SHEN Jiao. Research status of biomarkers related to the efficacy of PD-1 inhibitors in the treatment of hepatocellular carcinoma[J]. Journal of Practical Oncology, 2022, 36(4): 374-380.

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.1002-3070.2022.04.016

http://journal09.magtechjournal.com/Jwk3_syzlxzz/CN/Y2022/V36/I4/374

参考文献

1 Sung H,Ferlay J,Siegel RL,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.
2 Tai D,Choo SP,Chew V.Rationale of immunotherapy in hepatocellular carcinoma and its potential biomarkers[J].Cancers(Basel),2019,11(12):1926.
3 Xu F,Jin T,Zhu Y,et al.Immune checkpoint therapy in liver cancer[J].Exp Clin Cancer Res,2018,37(1):110.
4 Petrella TM,Robert C,Richtig E,et al.Patient-reported outcomes in KEYNOTE-006,a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma[J].Eur J Cancer,2017,86:115-124.
5 Feun LG,Li YY,Wu C,et al.Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced,unresectable hepatoce llular carcinoma[J].Cancer,2019,125(20):3603-3614.
6 El-Khoueiry AB,Sangro B,Yau T,et al.Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate 040):an open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J].Lancet,2017,389(10088):2492-2502.
7 Liu CQ,Xu J,Zhou ZG,et al.Expression patterns of programmed death ligand 1 correlate with different microenvironments and patient prognosis in hepatoce llular carcinoma[J].Br J Cancer,2018,119(1):80-88.
8 Pinato DJ,Mauri FA,Spina P,et al.Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma:the Blueprint-HCC study[J].Br J Cancer,2019,120(11):1033-1036.
9 Galuppini F,Dal Pozzo CA,Deckert J,et al.Tumor mutation burden:from comprehensive mutational screening to the clinic[J].Cancer Cell Int,2019,19:209.
10 Jang BS,Han W,Kim IA.Tumor mutation burden,immune checkpoint crosstalk and radiosensitivity in single-cell RNA sequencing data of breast cancer[J].Radiother Oncol,2020,142:202-209.
11 Xu J,Zhang Y,Jia R,et al.Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma,gastric,or esophagogastric junction cancer:an open-label,dose escalation and expansion study[J].Clin Cancer Res,2019,25(2):515-523.
12 Huo J,Wu L,Zang Y.A Prognostic model of 15 immune-related gene Pairs associated with tumor mutation burden for hepatocellular carcinoma[J].Front Mol Biosci,2020,7:581354.
13 Li Z,Pearlman AH,Hsieh P.DNA mismatch repair and the DNA damage response[J].DNA Repair(Amst),2016,38:94-101.
14 Ang C,Klempner SJ,Ali SM,et al.Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma[J].Oncotarget,2019,10(40):4018-4025.
15 Meng L,Ma R,Yan R,et al.Profiles of immune infiltration in the tumor microenvironment of hepatocellular carcinoma[J].J Gastrointest Oncol,2021,12(3):1152-1163.
16 Zheng X,Jin W,Wang S,et al.Progression on the roles and mechanisms of tumor-infiltrating T lymphocytes in patients with hepatocellular carcinoma[J].Front Immunol,2021,12:729705.
17 Kaseb AO,Vence L,Blando J,et al.Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma[J].Cancer Immunol Res,2019,7(9):1390-1395.
18 Hsu CL,Ou DL,Bai LY,et al.Exploring markers of exhausted CD8 T cells to predict response to immune checkpoint inhibitor therapy for hepatocellular carcinoma[J].Liver Cancer,2021,10(4):346-359.
19 Siddiqui I,Schaeuble K,Chennupati V,et al.Intratumoral Tcf1+PD-1+ CD8⁺T Cells with stem-like properties promote tumor control in response to vac cination and checkpoint blockade immunotherapy[J].Immunity,2019,50(1):195-211.
20 Ng HHM,Lee RY,Goh S,et al.Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immun otherapy in hepatocellular carcinoma[J].J Immunother Cancer,2020,8(2):987.
21 Ayers M,Lunceford J,Nebozhyn M,et al.IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade[J].J Clin Invest,2017,127(8):2930-2940.
22 Brown ZJ,Fu Q,Ma C,et al.Carnitine palmitoyltransferase gene upregulation by linoleic acid induces CD4⁺T cell apoptosis promoting HCC development[J].Cell Death Dis,2018,9(6):620.
23 Lin SZ,Chen KJ,Xu ZY,et al.Prediction of recurrence and survival in hepatocellular carcinoma based on two Cox models mainly determined by FoxP3+ regulatory T cells[J].Cancer Prev Res(Phila),2013,6(6):594-602.
24 Ding W,Xu X,Qian Y,et al.Prognostic value of tumor-infiltrating lymphocyte in hepatocellular carcinoma:a meta-analysis[J].Medicine(Baltimore),2018,97(50):13301.
25 Kuang DM,Peng C,Zhao Q,et al.Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells[J].Hepatology,2010,51(1):154-164.
26 Zhang H,Deng T,Liu R,et al.CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer[J].Mol Cancer,2020,19(1):43.
27 Han Q,Zhao H,Jiang Y,et al.HCC-Derived Exosomes:critical player and target for cancer immune escape[J].Cells,2019,8(6):558.
28 Li X,Lei Y,Wu M,et al.Regulation of macrophage activation and polarization by HCC-derived exosomal lncRNA TUC339[J].Int J Mol Sci,2018,19(10):2958.
29 Liu J,Fan L,Yu H,et al.Endoplasmic reticulum stress causes liver cancer cells to release exosomal miR-23a-3p and Up-regulate programmed death ligand 1 expression in macrophages[J].Hepatology,2019,70(1):241-258.
30 Khemlina G,Ikeda S,Kurzrock R.The biology of Hepatocellular carcinoma:implications for genomic and immune therapies[J].Mol Cancer,2017,16(1):149.
31 Jiang H,Ning G,Wang Y,et al.Identification of an m6A-Related signature as biomarker for hepatocellular carcinoma prognosis and correlates with sorafenib and anti-PD-1 immunotherapy treatment response[J].Dis Markers,2021,2021:5576683.
32 Chui NN,Cheu JW,Yuen VW,et al.Inhibition of CMTM4 sensitizes cholang-iocarcinoma and hepatocellular carcinoma to T cell-mediated antitumor immunity through PD-L1[J].Hepatol Commun,2022,6(1):178-193.
33 Harding JJ,Nandakumar S,Armenia J,et al.Prospective genotyping of hepatocellular carcinoma:clinical implications of next-generation sequencing for matching patients to targeted and immune therapies[J].Clin Cancer Res,2019,25(7):2116-2126.
34 Shao YY,Liu TH,Hsu C,et al.Early alpha-foetoprotein response associated with treatment efficacy of immune checkpoint inhibitors for advanced hepato cellular carcinoma[J].Liver Int,2019,39(11):2184-2189.
35 Park SJ,Jang JY,Jeong SW,et al.Usefulness of AFP,AFP-L3,and PIVKA-II,and their combinations in diagnosing hepatocellular carcinoma[J].Medicine(Baltimore),2017,96(11):5811.
36 Feng H,Li B,Li Z,et al.PIVKA-II serves as a potential biomarker that complements AFP for the diagnosis of hepatocellular carcinoma[J].BMC Cancer,2021,21(1):401.
37 Sun X,Mei J,Lin W,et al.Reductions in AFP and PIVKA-II can predict the efficiency of anti-PD-1 immunotherapy in HCC patients[J].BMC Cancer,2021,21(1):775.
38 Chen J,Gingold JA,Su X.Immunomodulatory TGF-β signaling in hepatocellular carcinoma[J].Trends Mol Med,2019,25(11):1010-1023.
39 Bao S,Jiang X,Jin S,et al.TGF-β1 Induces immune escape by enhancing PD-1 and CTLA-4 expression on T lymphocytes in hepatocellular carcinoma[J].Front Oncol,2021,11:694145.
40 Dharmapuri S,Özbek U,Lin JY,et al.Predictive value of neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in advanced hepatocellular carcinoma patients treated with anti-PD-1 therapy[J].Cancer Med,2020,9(14):4962-4970.
41 Mei J,Sun XQ,Lin WP,et al.Comparison of the prognostic value of inflammation-based scores in patients with hepatocellular carcinoma after anti-PD-1 therapy[J].J Inflamm Res,2021,14:3879-3890.
42 Schobert IT,Savic LJ,Chapiro J,et al.Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictors of tumor response in hepatocellular carcinoma after DEB-TACE[J].Eur Radiol,2020,30(10):5663-5673.
43 Zheng Y,Wang T,Tu X,et al.Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma[J].Immunother Cancer,2019,7(1):193.
44 Li L,Ye J.Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors:a Chinese population based study[J].Medicine(Baltimore),2020,99(37):21788.
45 Xu L,Leng C,Chen L,et al.Hypothyroidism is a predictive factor of superior antitumour efficacy of programmed death 1 inhibitors in hepatocellular carcinma[J].Int J Cancer,2022,150(3):472-481.
46 Lin YH,Lin KH,Yeh CT.Thyroid hormone in hepatocellular carcinoma:cancer risk,growth regulation,and anticancer drug resistance[J].Front Med(Lausanne),2020,7:174.
47 Akce M,Liu Y,Zakka K,et al.Impact of sarcopenia,BMI,and inflammatory biomarkers on survival in advanced hepatocellular carcinoma treated with anti-PD-1 antibody[J].Am J Clin Oncol,2021,44(2):74-81.
48 Cortellini A,Bersanelli M,Buti S,et al.A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors:when overweight becomes favorable[J].Immunother Cancer,2019,7(1):57.
49 Nakanishi Y,Masuda T,Yamaguchi K,et al.Albumin-globulin ratio is a predictive biomarker of antitumor effect of anti-PD-1 antibody in patients with non-small cell lung cancer[J].Int J Clin Oncol,2020,25(1):74-81.
50 Aoki T,Nishida N,Ueshima K,et al.Higher enhancement intrahepatic nodules on the hepatobiliary phase of Gd-EOB-DTPA-Enhanced MRI as a poor responsive marker of Anti-PD-1/PD-L1 monotherapy for unresectable hepa-tocellular carcinoma[J].Liver Cancer,2021,10(6):615-628.
51 Ueno A,Masugi Y,Yamazaki K,et al.OATP1B3 expression is strongly associated with Wnt/β-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma[J].Hepatol,2014,61(5):1080-1087.
52 Zou Y,Ruan S,Jin L,et al.CDK1,CCNB1,and CCNB2 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma[J].Med Sci Monit,2020,26:925289.
53 Wang Y,Cao K.KDM1A promotes immunosuppression in hepatocellular carcinoma by regulating PD-L1 through Demethylating MEF2D[J].Immunol Res,2021,2021:9965099.

[1]	连晓敏, 马峰, 赵丽霞, 孟玮, 赵丹丹, 赵峻峰. PD-1抑制剂联合抗血管生成药物及化疗二线治疗晚期肺腺癌的临床对比分析[J]. 实用肿瘤学杂志, 2022, 36(4): 339-345.
[2]	刘嘉铭, 崔逸峰, 陆朝阳. 槐耳清膏通过线粒体转录因子A调控Akt信号通路进而抑制肝细胞癌的增殖和转移[J]. 实用肿瘤学杂志, 2022, 36(3): 203-207.
[3]	刘雨, 俞星新, 耿志达, 陈政良, 惠鹏, 梁英健. 成纤维细胞在肝癌发生发展中的作用[J]. 实用肿瘤学杂志, 2022, 36(2): 167-172.
[4]	王宗文, 李小东, 朱乾坤, 曾世聪, 翟博. KIF14在肝细胞癌SMCC-7721获得性耐药机制中的研究[J]. 实用肿瘤学杂志, 2022, 36(1): 14-19.
[5]	刘菲, 隋红. 基于肿瘤免疫微环境的肝癌分子分型研究进展[J]. 实用肿瘤学杂志, 2021, 35(6): 557-561.
[6]	纪雷, 纪道林, 鲍冬冬, 谭刚. lncRNA在肝细胞癌索拉非尼耐药中的最新研究进展[J]. 实用肿瘤学杂志, 2021, 35(6): 562-567.
[7]	赵浩然, 李满, 张玉宝. 肝细胞癌相关RNA结合蛋白研究进展[J]. 实用肿瘤学杂志, 2021, 35(6): 576-579.
[8]	贺玲, 姚克铖. 糖基磷脂酰肌醇转酰胺酶与肝癌[J]. 实用肿瘤学杂志, 2021, 35(5): 458-461.
[9]	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.
[10]	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.
[11]	曲雁飞, 刘超, 王勃军, 方琳, 张艳桥. CSN6基因在肝细胞癌组织中的表达及临床意义[J]. 实用肿瘤学杂志, 2019, 33(4): 328-333.
[12]	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.
[13]	赵凌云, 齐鲁楠, 游雪梅审校. 热休克蛋白70在肝细胞癌中的研究进展[J]. 实用肿瘤学杂志, 2017, 31(6): 528-532.
[14]	赵孟雷. 番茄红素对人肝癌HepG2细胞增殖和凋亡的影响[J]. 实用肿瘤学杂志, 2017, 31(3): 211-216.
[15]	李世杰, 杨奕, 田玉龙, 侯继野, 刘瑞宝. TACE后残余肝癌细胞β-catenin和p28GANK的表达及意义的研究[J]. 实用肿瘤学杂志, 2016, 30(5): 430-435.