ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 36 Issue 6
Jun.  2020
Turn off MathJax
Article Contents

Predictive factors for the clinical effect of PD-1/PD-L1 checkpoint inhibitors in treatment of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2020.06.044
  • Published Date: 2020-06-20
  • At present,there is still a lack of uniform treatment strategies for hepatocellular carcinoma( HCC). Immunotherapy,especially PD-1/PD-L1 checkpoint inhibitors,is a novel therapy for HCC and can bring survival benefits to patients with advanced HCC. However,research data show that only a small number of HCC patients can benefit from this treatment regimen. To date,few biomarkers have been reported to predict the clinical effect of PD-1/PD-L1 checkpoint inhibitors in HCC patients. This article reviews the biomarkers studied for HCC and other tumors and explores the possible predictive factors for the clinical effect of PD-1/PD-L1 checkpoint inhibitors in HCC,in order to optimize the selection of treatment population and improve the clinical effect of PD-1/PD-L1 checkpoint inhibitors in the treatment of HCC.


  • loading
  • [1] SIEGEL RL,MILLER KD,JEMAL A. Cancer statistics,2017[J]. CA Cancer J Clin,2017,67(1):7-30.
    [2] IKEDA M,MORIZANE C,UENO M,et al. Chemotherapy for hepatocellular carcinoma:Current status and future perspectives[J]. Jpn J Clin Oncol,2018,48(2):103-114.
    [3] JENNE CN,KUBES P. Immune surveillance by the liver[J].Nat Immunol,2013,14(10):996-1006.
    [4] BOWEN DG,ZEN M,HOLZ L,et al. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity[J]. J Clin Invest,2004,114(15):701-712.
    [5] NISHIDA N,KUDO M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication[J]. Oncology,2017,92(Suppl 1):40-49.
    [6] LEE S,LOECHER M,IYER R. Immunomodulation in hepatocellular cancer[J]. J Gastrointest Oncol,2018,9(1):208-219.
    [7] WELLENSTEIN MD,de VISSER KE. Cancer-cell-intrinsic mechanisms shaping the tumor immune landscape[J]. Immunity,2018,48(3):399-416.
    [8] HATO T,GOYAL L,GRETEN TF,et al. Immune checkpoint blockade in hepatocellular carcinoma:Current progress and future directions[J]. Hepatology,2014,60(5):1776-1782.
    [9] FREEMAN GJ,LONG AJ,IWAI Y,et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 familymember leads to negative regulation of lymphocyte activation[J]. J Exp Med,2000,192(7):1027-1034.
    [10] PARDOLL DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer,2012,12(4):252-264.
    [11] SHRESTHA R,PRITHVIRAJ P,ANAKA M,et al. Monitoring immune checkpoint regulators as predictive biomarkers in hepatocellular carcinoma[J]. Front Oncol,2018,13(8):269.
    [12] NISHIDA N,KUDO M. Liver damage related to immune checkpoint inhibitors[J]. Hepatol Int,2019,13(3):248-252.
    [13] HERBST RS,SORIA JC,KOWANETZ M,et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[J]. Nature,2014,515(7528):563-567.
    [14] EL-KHOUEIRY AB,SANGRO B,YAU T,et al. Nivolumab in patients with advanced hepatocellular carcinoma(CheckMate040):An open-label,non-comparative,phase 1/2 dose escalation and expansion trial[J]. Lancet, 2017, 389(10088):2492-2502.
    [15] POWLES T,EDER JP,FINE GD,et al. MPDL3280A(antiPD-L1)treatment leads to clinical activity in metastatic bladder cancer[J]. Nature,2014,515(7528):558-562.
    [16] YI M,JIAO D,XU H,et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors[J]. Mol Cancer,2018,17(1):129.
    [17] YU H,BATENCHUK C,BADZIO A,et al. PD-L1 expression by two complementary diagnostic assays and mRNA in situ hybridization in small cell lung cancer[J]. J Thorac Oncol,2017,12(1):110-120.
    [18] VOGELSTEIN B,PAPADOPOULOS N,VELCULESCU VE,et al. Cancer genome landscapes[J]. Science,2013,339(6127):1546-1558.
    [19] CONSTANTINIDOU A,ALIFIERIS C,TRAFALIS DT. Targeting programmed cell death-1(PD-1)and Ligand(PD-L1):A new era in cancer active immunotherapy[J]. Pharmacol Ther,2019,194:84-106.
    [20] GOODAMAN 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.
    [21] BRADLEY SD,CHEN Z,MELENDEZ B,et al. BRAFV600E co-opts a conserved MHC class I internalization pathway to diminish antigen presentation and CD8+T-cell recognition of melanoma[J]. Cancer Immunol Res,2015,3(6):602-609.
    [22] SELIGER B,HARDERS C,WOLLSCHEID U,et al. Suppression of MHC class I antigens in oncogenic transformants:Association with decreased recognition by cytotoxic T lymphocytes[J]. Exp Hematol,1996,24(11):1275-1279.
    [23] 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.
    [24] BOYIADZIS MM,KIRKWOOD JM,MARSHALL JL,et al. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease[J]. J Immunother Cancer,2018,6(1):35.
    [25] GOUMARD C,DESBOIS-MOUTHON C,WENDUM D,et al.Low levels of microsatellite instability at simple repeated sequences commonly occur in human hepatocellular carcinoma[J]. Cancer Genom Proteom,2017,14(5):329-339.
    [26] JENKINS RW,BARBIE DA,FLAHERTY KT. Mechanisms of resistance to immune checkpoint inhibitors[J]. Br J Cancer,2018,118(1):9-16.
    [27] WU X,GU Z,CHEN Y,et al. Application of PD-1 blockade in cancer immunotherapy[J]. Comput Struct Biotechnol J,2019,17:661-674.
    [28] DANILOVA L,WANG H,SUNSHINE J,et al. Association of PD-1/PD-L axis expression with cytolytic activity,mutational load,and prognosis in melanoma and other solid tumors[J]. Proc Natl Acad Sci USA,2016,113(48):e7769-e7777.
    [29] 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.
    [30] SCHMETTERER KG,PICKL WF. The IL-10/STAT3 axis:Contributions to immune tolerance by thymus and peripherally derived regulatory T-cells[J]. Eur J Immunol,2017,47(8):1256-1265.
    [31] HONG JW,LIM JH,CHUNG CJ,et al. Immune toleranceof human dental pulp-derived mesenchymal stem cells mediated by CD4(+)CD25(+)FoxP3(+)regulatory T-cells and induced by TGF-beta1 and IL-10[J]. Yonsei Med J,2017,58(5):1031-1039.
    [32] CROWLEY E,di NICOLANTONIO F,LOUPAKIS F,et al. Liquid biopsy:Monitoring cancer-genetics in the blood[J]. Nat Rev Clin Oncol,2013,10(8):472-484.
    [33] HENCH IB,HENCH J,TOLNAY M. Liquid biopsy in clinical management of breast,lung,and colorectal cancer[J]. Front Med(Lausanne),2018,5:9.
    [34] NAKAYA A,KURATA T,YOSHIOKA H,et al. Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab[J]. Int J Clin Oncol,2018,23(4):634-640.
    [35] ZHOU G,SPRENGERS D,BOOR P,et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas[J]. Gastroenterology,2017,153(4):1107-1119. e10.
    [36] FEUN LG,LI YY,WU C,et al. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma[J].Cancer,2019,125(20):3603-3614.
    [37] FINKELMEIER F,CANLI,TAL A,et al. High levels of the soluble programmed death-ligand(sPD-L1)identify hepatocellular carcinoma patients with a poor prognosis[J]. Eur J Cancer,2016,59:152-159.
    [38] CHEN G,HUANG AC,ZHANG W,et al. Exosomal PD-L1contributes to immunosuppression and is associated with anti-PD-1 response[J]. Nature,2018,560(7718):382-386.
    [39] KHAGI Y,GOODMAN AM,DANIELS GA,et al. Hypermutated circulating tumor DNA:Correlation with response to checkpoint inhibitor-based immunotherapy[J]. Clin Cancer Res,2017,23(19):5729-5736.
    [40] YU LX,SCHWABE RF. The gut microbiome and liver cancer:mechanisms and clinical translation[J]. Nature Rev Gastroenterol Hepatol,2017,14(9):527-539.
    [41] ROUTY B,LE CHATELIER E,DEROSA L,et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors[J]. Science,2018,359(6371):91-97.
    [42] SOULARUE E,LEPAGE P,COLOMBEL JF,et al. Enterocolitis due to immune checkpoint inhibitors:A systematic review[J].Gut,2018,67(11):2056-2067.
    [43] CONFORTI F,PALA L,BAGNARDI V,et al. Cancer immunotherapy efficacy and patients'sex:A systematic review and meta-analysis[J]. Lancet Oncol,2018,19(6):737-746.
    [44] NOSRATI A,TSAI KK,GOLDINGER SM,et al. Evaluation of clinicopathological factors in PD-1 response:Derivation and validation of a prediction scale for response to PD-1 monotherapy[J]. Br J Cancer,2017,116(9):1141-1147.
    [45] KUGEL CH 3rd,DOUGLASS SM,WEBSTER MR,et al. Age Correlates with response to anti-PD1,reflecting age-related differences in intratumoral effector and regulatory T-cell populations[J]. Clin Cancer Res,2018,24(21):5347-5356.
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Article Metrics

    Article views (552) PDF downloads(127) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint