Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Hepatology International
Published in: Hepatology International 1/2020

01-01-2020 | Hepatocellular Carcinoma | Original Article

Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma

Authors: Jing Liao, Dan-Ni Zeng, Jin-Zhu Li, Qiao-Min Hua, Zhiyu Xiao, Chuanchao He, Kai Mao, Ling-Yan Zhu, Yifan Chu, Wei-Ping Wen, Limin Zheng, Yan Wu

Published in: Hepatology International | Issue 1/2020

Login to get access

Abstract

Background

Sorafenib is the most widely used first-line treatment for patients with advanced hepatocellular carcinoma (HCC), but such treatment provides only limited survival benefits that might be related to the immune status of distinct tumor microenvironments. A fundamental understanding of the distribution and phenotypes of T lymphocytes in tumors will undoubtedly lead to the development of novel immunotherapeutic strategies that could possibly enhance the efficacy of sorafenib treatments.

Methods

Flow cytometry, immunohistochemistry and immunofluorescence analyses were performed to detect the infiltration and distribution of various leukocyte populations, and the expression of different immune checkpoint molecules in fresh HCC tumor tissues. Correlations among indicating genes were calculated in 365 patients with HCC from The Cancer Genome Atlas (TCGA) data set, and the cumulative overall survival time was calculated using the Kaplan–Meier method. Moreover, role of adenosinergic pathway on sorafenib anti-tumor efficacy was investigated using both subcutaneous and orthotopic transplantation tumor model in immune competent C57BL/6 mice.

Results

We revealed that levels of CD3+ and CD8+ T cells were significantly downregulated in HCC tumor tissue, so were the infiltration of CD169+ cells (a Mφ subpopulation with T cell activation capacities) and their contact with CD8+ cells in tumor milieus. Moreover, levels of PD-1 and CD39 expression were significantly upregulated in human HCC-infiltrating CD4+ and CD8+ T cells, and CD39+CD8+ T cells exhibited a CD69+PD-1+perforinlowIFNγlow “exhausted” phenotype. Levels of both CD39+ T cells infiltration and adenosine receptor ADORA2B expression in tumor tissues were negatively correlated with overall survival of patients with HCC. Accordingly, mice treated with sorafenib in combination with adenosine A2B receptor blockage reagents exhibited significantly reduced tumor progression compared with control groups.

Conclusions

These results suggest that adenosinergic pathway might represent an applicable target for sorafenib-combined-therapies in human HCC.
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMed
2.
Dawkins J, Webster RM. The hepatocellular carcinoma market. Nat Rev Drug Discov. 2019;18(1):13–4.PubMed
3.
Bishayee A. The role of inflammation and liver cancer. Adv Exp Med Biol. 2014;816:401–35.PubMed
4.
Buonaguro L, Mauriello A, Cavalluzzo B, Petrizzo A, Tagliamonte M. Immunotherapy in hepatocellular carcinoma. Ann Hepatol. 2019;18(2):291–7.PubMed
5.
Arzumanyan A, Reis HM, Feitelson MA. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat Rev Cancer. 2013;13(2):123–35.PubMed
6.
Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.PubMed
7.
European Association For The Study Of The L, European Organisation For R, Treatment Of C. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56(4):908–43.
8.
Chen ML, Yan BS, Lu WC, Chen MH, Yu SL, Yang PC, et al. Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity. Int J Cancer. 2014;134(2):319–31.PubMed
9.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.PubMed
10.
Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013;14(10):1014–22.PubMedPubMedCentral
11.
He M, Li Q, Zou R, Shen J, Fang W, Tan G, et al. Sorafenib plus hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin vs sorafenib alone for hepatocellular carcinoma with portal vein invasion: a randomized clinical trial. JAMA Oncol. 2019;5(7):953–60.PubMedPubMedCentral
12.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.PubMed
13.
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.PubMedPubMedCentral
14.
Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–26.PubMedPubMedCentral
15.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502.PubMedPubMedCentral
16.
Siu LL, Ivy SP, Dixon EL, Gravell AE, Reeves SA, Rosner GL. Challenges and opportunities in adapting clinical trial design for immunotherapies. Clin Cancer Res. 2017;23(17):4950–8.PubMedPubMedCentral
17.
Vijayan D, Young A, Teng MWL, Smyth MJ. Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer. 2017;17(12):709–24.PubMed
18.
Di Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2017;36(3):293–303.PubMed
19.
Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev. 2017;276(1):121–44.PubMedPubMedCentral
20.
Perrot I, Michaud HA, Giraudon-Paoli M, Augier S, Docquier A, Gros L, et al. Blocking antibodies targeting the CD39/CD73 immunosuppressive pathway unleash immune responses in combination cancer therapies. Cell Rep. 2019;27(8):2411–2425.e9.PubMed
21.
Camp RL, Dolled-Filhart M, Rimm DL. X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res. 2004;10(21):7252–9.PubMed
22.
Chu Y, Liao J, Li J, Wang Y, Yu J, Wang J, et al. CD103+ tumor-infiltrating lymphocytes predict favorable prognosis in patients with esophageal squamous cell carcinoma. J Cancer. 2019;10(21):5234–43.PubMedPubMedCentral
23.
Zhang Y, Li JQ, Jiang ZZ, Li L, Wu Y, Zheng L. CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma. J Pathol. 2016;239(2):231–41.PubMed
24.
Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, et al. CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011;34(1):85–95.PubMed
25.
Martinez-Pomares L, Gordon S. CD169+ macrophages at the crossroads of antigen presentation. Trends Immunol. 2012;33(2):66–70.PubMed
26.
27.
Noble A, Mehta H, Lovell A, Papaioannou E, Fairbanks L. IL-12 and IL-4 activate a CD39-dependent intrinsic peripheral tolerance mechanism in CD8(+) T cells. Eur J Immunol. 2016;46(6):1438–48.PubMedPubMedCentral
28.
Gouttefangeas C, Mansur I, Schmid M, Dastot H, Gelin C, Mahouy G, et al. The CD39 molecule defines distinct cytotoxic subsets within alloactivated human CD8-positive cells. Eur J Immunol. 1992;22(10):2681–5.PubMed
29.
Simoni Y, Becht E, Fehlings M, Loh CY, Koo SL, Teng KWW, et al. Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature. 2018;557(7706):575–9.PubMed
30.
Canale FP, Ramello MC, Nunez N, Araujo Furlan CL, Bossio SN, Gorosito Serran M, et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8(+) T cells. Cancer Res. 2018;78(1):115–28.PubMed
31.
Raoul JL, Kudo M, Finn RS, Edeline J, Reig M, Galle PR. Systemic therapy for intermediate and advanced hepatocellular carcinoma: sorafenib and beyond. Cancer Treat Rev. 2018;68:16–24.PubMed
32.
Llovet JM, Montal R, Sia D, Finn RS. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol. 2018;15(10):599–616.PubMed
33.
Fu YP, Yi Y, Cai XY, Sun J, Ni XC, He HW, et al. Overexpression of interleukin-35 associates with hepatocellular carcinoma aggressiveness and recurrence after curative resection. Br J Cancer. 2016;114(7):767–76.PubMedPubMedCentral
34.
Ma XL, Shen MN, Hu B, Wang BL, Yang WJ, Lv LH, et al. CD73 promotes hepatocellular carcinoma progression and metastasis via activating PI3K/AKT signaling by inducing Rap1-mediated membrane localization of P110beta and predicts poor prognosis. J Hematol Oncol. 2019;12(1):37.PubMedPubMedCentral
35.
Liao J, Luan Y, Ren Z, Liu X, Xue D, Xu H, et al. Converting lymphoma cells into potent antigen-presenting cells for interferon-induced tumor regression. Cancer Immunol Res. 2017;5(7):560–70.PubMedPubMedCentral
36.
Sun C, Xu J, Song J, Liu C, Wang J, Weng C, et al. The predictive value of centre tumour CD8(+) T cells in patients with hepatocellular carcinoma: comparison with immunoscore. Oncotarget. 2015;6(34):35602–15.PubMedPubMedCentral
37.
Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013;25(2):214–21.PubMedPubMedCentral
38.
Xu MM, Pu Y, Zhang Y, Fu YX. The role of adaptive immunity in the efficacy of targeted cancer therapies. Trends Immunol. 2016;37(2):141–53.PubMedPubMedCentral
39.
40.
41.
Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257–65.PubMedPubMedCentral
42.
Bloy N, Pol J, Manic G, Vitale I, Eggermont A, Galon J, et al. Trial watch: radioimmunotherapy for oncological indications. Oncoimmunology. 2014;3(9):e954929.PubMedPubMedCentral
43.
Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14.PubMedPubMedCentral
44.
Seebacher NA, Stacy AE, Porter GM, Merlot AM. Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res. 2019;38(1):156.PubMedPubMedCentral
45.
46.
Binnewies M, Roberts EW, Kersten K, Chan V, Fearon DF, Merad M, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018;24(5):541–50.PubMedPubMedCentral
47.
Tang H, Fu YX. Immune evasion in tumor’s own sweet way. Cell Metab. 2018;27(5):945–6.PubMed
48.
Wang L, Wang FS. Clinical immunology and immunotherapy for hepatocellular carcinoma: current progress and challenges. Hepatol Int. 2019;13(5):521–33.PubMed
49.
Couri T, Pillai A. Goals and targets for personalized therapy for HCC. Hepatol Int. 2019;13(2):125–37.PubMed
50.
Nishida N, Kudo M. Liver damage related to immune checkpoint inhibitors. Hepatol Int. 2019;13(3):248–52.PubMed
51.
Maj T, Wang W, Crespo J, Zhang H, Wang W, Wei S, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol. 2017;18(12):1332–41.PubMedPubMedCentral
Metadata
Title
Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma
Authors
Jing Liao
Dan-Ni Zeng
Jin-Zhu Li
Qiao-Min Hua
Zhiyu Xiao
Chuanchao He
Kai Mao
Ling-Yan Zhu
Yifan Chu
Wei-Ping Wen
Limin Zheng
Yan Wu
Publication date
01-01-2020
Publisher
Springer India
Published in
Hepatology International / Issue 1/2020
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-019-10003-2

Other articles of this Issue 1/2020

Hepatology International 1/2020 Go to the issue

Review Article

Antimicrobial resistance in chronic liver disease

Original Article

Tenofovir versus entecavir in lowering the risk of hepatocellular carcinoma development in patients with chronic hepatitis B: a critical systematic review and meta-analysis

Original Article

Retrospective comparison of EASL 2018 and LI-RADS 2018 for the noninvasive diagnosis of hepatocellular carcinoma using magnetic resonance imaging

Original Article

Ascitic fluid infection in children with liver disease: time to change empirical antibiotic policy

Original Article

Dynamic changes of T cell receptor repertoires in patients with hepatitis B virus-related acute-on-chronic liver failure

Original Article

Improving pathological early diagnosis and differential biomarker value for hepatocellular carcinoma via RNAscope technology

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits