Skip to main content

Advertisement

SpringerLink
Log in

Post-transplant inflammatory cytokine signature adds value for predicting tumor recurrence after liver transplantation for hepatocellular carcinoma

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 29 April 2024

Abstract

Background

Cytokines are key regulators of post-transplant inflammation responses which reconstitute post-transplant hepatic and systemic environments to influence the likelihood of tumor relapse. This study investigated the prognostic value of post-transplant cytokines on tumor recurrence after liver transplantation (LT) for hepatocellular carcinoma (HCC).

Methods

A retrospective analysis was conducted in prospectively collected 150 adult HCC patients who received liver transplantation from 1997 to 2015. The post-transplant 41 inflammatory cytokines were quantified by multiplexing analysis and determined their prognostic value for predicting post-LT tumor recurrence by receiver operative characteristic analysis. A prediction model for post-LT tumor recurrence was generated by the logistic regression and internally validated Bootstrapping and compared with external prediction models.

Results

Post-transplant circulating CCL11, IFNα2, and IL17A cytokines were identified to be significant predictors of post-LT tumor recurrence and survival. A prediction score composed of the post-transplant 3-cytokine (P3C) signature, UCSF criteria, and pre-LT AFP was established. The P3C-UCSF-AFP score significantly predicted post-LT tumor recurrence and poor survival both in deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). The P3C-UCSF-AFP score was validated to significantly predict post-LT 2-year and 5-year tumor recurrence, outperforming the RETREAT score, French AFP model, up-to-seven, UCSF criteria, and Milan criteria. Importantly, the P3C-UCSF-AFP score could cost-effectively stratify high-risk recipients subjected to a refinement of post-recurrence survival.

Conclusion

The integrated P3C-UCSF-AFP score not only compensated for the pre-LT unpredictability and predicted post-LT tumor recurrence accurately, but also guided the clinical refinements of post-LT surveillance and therapeutic strategies in transplant oncology.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data Availability

Data generated or analyzed during this study are available from the corresponding author on reasonable request.

References

  1. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–1462

    Article  CAS  PubMed  Google Scholar 

  2. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017;14(4):203–217

    Article  PubMed  Google Scholar 

  3. McVey JC, Sasaki K, Firl DJ. Risk assessment criteria in liver transplantation for hepatocellular carcinoma: proposal to improve transplant oncology. Hepat Oncol. 2020;7(3):HEP26

    Article  PubMed  PubMed Central  Google Scholar 

  4. Berenguer M, Burra P, Ghobrial M, Hibi T, Metselaar H, Sapisochin G, et al. Post-transplant management of recipients undergoing liver transplantation for hepatocellular carcinoma. Working group report from the ILTS transplant oncology consensus conference. Transplantation. 2020;104(6):1143–1149

    Article  PubMed  Google Scholar 

  5. Liu Z, Liu Y, Zhang W, Hong Y, Meng J, Wang J, et al. Deep learning for prediction of hepatocellular carcinoma recurrence after resection or liver transplantation: a discovery and validation study. Hepatol Int. 2022;16(3):577–589

    Article  CAS  PubMed  Google Scholar 

  6. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693–699

    Article  CAS  PubMed  Google Scholar 

  7. Al-Ameri AAM, Wei X, Wen X, Wei Q, Guo H, Zheng S, et al. Systematic review: risk prediction models for recurrence of hepatocellular carcinoma after liver transplantation. Transpl Int. 2020;33(7):697–712

    Article  PubMed  Google Scholar 

  8. Liu H, Man K. New insights in mechanisms and therapeutics for short- and long-term impacts of hepatic ischemia reperfusion injury post liver transplantation. Int J Mol Sci. 2021;22(15):8210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Li CX, Ling CC, Shao Y, Xu A, Li XC, Ng KT, et al. CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation. J Hepatol. 2016;65(5):944–952

    Article  CAS  PubMed  Google Scholar 

  10. Ling CC, Ng KT, Shao Y, Geng W, Xiao JW, Liu H, et al. Post-transplant endothelial progenitor cell mobilization via CXCL10/CXCR3 signaling promotes liver tumor growth. J Hepatol. 2014;60(1):103–109

    Article  CAS  PubMed  Google Scholar 

  11. Man K, Lo CM, Xiao JW, Ng KT, Sun BS, Ng IO, et al. The significance of acute phase small-for-size graft injury on tumor growth and invasiveness after liver transplantation. Ann Surg. 2008;247(6):1049–1057

    Article  PubMed  Google Scholar 

  12. Liu J, Lo CM, Man K. Role of intrahepatic regional immunity in post-transplant cancer recurrence. Engineering. 2022;10:57–64

    Article  CAS  Google Scholar 

  13. Lo CM, Fan ST, Liu CL, Chan SC, Ng IO, Wong J. Living donor versus deceased donor liver transplantation for early irresectable hepatocellular carcinoma. Br J Surg. 2007;94(1):78–86

    Article  CAS  PubMed  Google Scholar 

  14. Akamatsu N, Kokudo N. Liver transplantation for hepatocellular carcinoma from living-donor vs. deceased donor. Hepatobiliary Surg Nutr. 2016;5(5):422–428

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kulik LM, Fisher RA, Rodrigo DR, Brown RS Jr, Freise CE, Shaked A, et al. Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort. Am J Transplant. 2012;12(11):2997–3007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Man K. Recurrent malignancy: are we pushing the envelope? Liver Transpl. 2017;23(S1):S81–S84

    Article  PubMed  Google Scholar 

  17. Sosa RA, Zarrinpar A, Rossetti M, Lassman CR, Naini BV, Datta N, et al. Early cytokine signatures of ischemia/reperfusion injury in human orthotopic liver transplantation. JCI Insight. 2016;1(20):e89679

    Article  PubMed  PubMed Central  Google Scholar 

  18. Refolo MG, Messa C, Guerra V, Carr BI, D’Alessandro R. Inflammatory mechanisms of HCC development. Cancers (Basel). 2020;12(3):641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pang L, Ng KT, Liu J, Yeung WO, Zhu J, Chiu TS, et al. Plasmacytoid dendritic cells recruited by HIF-1alpha/eADO/ADORA1 signaling induce immunosuppression in hepatocellular carcinoma. Cancer Lett. 2021;522:80–92

    Article  CAS  PubMed  Google Scholar 

  20. Sun R, Zhang L, Yang Z, Zhou K, Tang H, Zhao W, et al. Liver transplantation for hepatocellular carcinoma: a prognostic model incorporating pretransplant inflammatory cytokines. Cytokine. 2022;153:155847

    Article  CAS  PubMed  Google Scholar 

  21. Hwang W, Lee J. Pathophysiologic Implications of cytokines secretion during liver transplantation surgery. Int J Med Sci. 2018;15(14):1737–1745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wong TC, Fung JYY, Cui TYS, Sin SL, Ma KW, She BWH, et al. The risk of going small: lowering GRWR and overcoming small-for-size syndrome in adult living donor liver transplantation. Ann Surg. 2021;274(6):e1260–e1268

    Article  PubMed  Google Scholar 

  23. Wong CS, Lee WC, Jenq CC, Tian YC, Chang MY, Lin CY, et al. Scoring short-term mortality after liver transplantation. Liver Transpl. 2010;16(2):138–146

    Article  PubMed  Google Scholar 

  24. Heinze G, Dunkler D. Five myths about variable selection. Transpl Int. 2017;30(1):6–10

    Article  PubMed  Google Scholar 

  25. Toniutto PFE, Fumolo E, Bitetto D. Risk factors for hepatocellular carcinoma recurrence after liver transplantation. Hepatoma Res. 2020;6:50

    CAS  Google Scholar 

  26. Elkomos BE, Abdo M, Mamdouh R, Abdelaal A. Can living donor liver transplantation provide similar outcomes to deceased-donor liver transplantation for hepatocellular carcinoma? A systematic review and meta-analysis. Hepatol Int. 2023;17(1):18–37

    Article  PubMed  Google Scholar 

  27. Boteon Y, Flores Carvalho MA, Panconesi R, Muiesan P, Schlegel A. Preventing tumour recurrence after liver transplantation: the role of machine perfusion. Int J Mol Sci. 2020;21(16):5791

    Article  PubMed  PubMed Central  Google Scholar 

  28. Shih KC, Man K. Small-for-size liver graft injury–impact on tumor behavior. Transplant Rev (Orlando). 2010;24(1):1–10

    Article  PubMed  Google Scholar 

  29. Verna EC, Patel YA, Aggarwal A, Desai AP, Frenette C, Pillai AA, et al. Liver transplantation for hepatocellular carcinoma: management after the transplant. Am J Transplant. 2020;20(2):333–347

    Article  PubMed  Google Scholar 

  30. Tabrizian P, Holzner ML, Mehta N, Halazun K, Agopian VG, Yao F, et al. Ten-year outcomes of liver transplant and downstaging for hepatocellular carcinoma. JAMA Surg. 2022;157(9):779–788

    PubMed  PubMed Central  Google Scholar 

  31. Lee DD, Sapisochin G, Mehta N, Gorgen A, Musto KR, Hajda H, et al. Surveillance for HCC after liver transplantation: increased monitoring may yield aggressive treatment options and improved postrecurrence survival. Transplantation. 2020;104(10):2105–2112

    Article  PubMed  Google Scholar 

  32. Roberts JP. Tumor surveillance-what can and should be done? Screening for recurrence of hepatocellular carcinoma after liver transplantation. Liver Transpl. 2005;2:S45–S46

    Article  Google Scholar 

  33. Mehta N, Heimbach J, Harnois DM, Sapisochin G, Dodge JL, Lee D, et al. Validation of a risk estimation of tumor recurrence after transplant (RETREAT) score for hepatocellular carcinoma recurrence after liver transplant. JAMA Oncol. 2017;3(4):493–500

    Article  PubMed  PubMed Central  Google Scholar 

  34. Aggarwal A, Te HS, Verna EC, Desai AP. A national survey of hepatocellular carcinoma surveillance practices following liver transplantation. Transplant Direct. 2021;7(1):e638

    Article  PubMed  Google Scholar 

  35. Parikh ND, Singal AG, Hutton DW, Tapper EB. Cost-effectiveness of hepatocellular carcinoma surveillance: an assessment of benefits and harms. Am J Gastroenterol. 2020;115(10):1642–1649

    Article  PubMed  PubMed Central  Google Scholar 

  36. Agarwal PD, Lucey MR. Management of hepatocellular carcinoma recurrence after liver transplantation. Ann Hepatol. 2022;27(1):100654

    Article  CAS  PubMed  Google Scholar 

  37. Wang R, Huang K. CCL11 increases the proportion of CD4+CD25+Foxp3+ Treg cells and the production of IL2 and TGFbeta by CD4+ T cells via the STAT5 signaling pathway. Mol Med Rep. 2020;21(6):2522–2532

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Taleb K, Auffray C, Villefroy P, Pereira A, Hosmalin A, Gaudry M, et al. Chronic type I IFN is sufficient to promote immunosuppression through accumulation of myeloid-derived suppressor cells. J Immunol. 2017;198(3):1156–1163

    Article  CAS  PubMed  Google Scholar 

  39. Pang L, Yeung OWH, Ng KTP, Liu H, Zhu J, Liu J, et al. Postoperative plasmacytoid dendritic cells secrete IFN-alpha to promote recruitment of myeloid-derived suppressor cells and drive hepatocellular carcinoma recurrence. Cancer Res. 2022.

  40. Itoh S, Kimura N, Axtell RC, Velotta JB, Gong Y, Wang X, et al. Interleukin-17 accelerates allograft rejection by suppressing regulatory T cell expansion. Circulation. 2011;124(11 Suppl):S187–S196

    CAS  PubMed  Google Scholar 

  41. Zhou Y, Yang X, Zhang H, Jiang J. The roles of T helper type 17/regulatory T cells in acute rejection after liver transplantation in rats. Transplantation. 2015;99(6):1126–1131

    Article  CAS  PubMed  Google Scholar 

  42. Bakos O, Lawson C, Rouleau S, Tai LH. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J Immunother Cancer. 2018;6(1):86

    Article  PubMed  PubMed Central  Google Scholar 

  43. Luo Y, Teng F, Fu H, Ding GS. Immunotherapy in liver transplantation for hepatocellular carcinoma: Pros and cons. World J Gastrointest Oncol. 2022;14(1):163–180

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by the grants from Theme-based Research Scheme (TRS: T12-703/19R), General Research Funding (GRFs: 17106921; 17124219; 17122517), and Collaborative Research Funding (CRFs: C7026-18G & C7021-21G) of Research Grants Council, and Seed Fund for Basic Research (201910159141 & 202011159038) of HKU, Hong Kong.

Author information

Authors and Affiliations

  1. Department of Surgery, School of Clinical Medicine, Faculty of Medicine, HKU-SZH & LKS, The University of Hong Kong, Hong Kong SAR, China

    Kevin Tak-Pan Ng, Jiang Liu, Oscar Wai-Ho Yeung, Li Pang, Hoi Chung Shiu, Hui Liu, Xin Xiang Yang, Albert Chi-Yan Chan, Tiffany Cho-Lam Wong, Chung Mau Lo & Kwan Man

  2. Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China

    Jiang Liu

Authors
  1. Kevin Tak-Pan Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Oscar Wai-Ho Yeung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hoi Chung Shiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xin Xiang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Albert Chi-Yan Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tiffany Cho-Lam Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chung Mau Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kwan Man
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JL, OW-HY, LP, HCS, HL, XXY, and AC-YC. The first draft of the manuscript was written by KT-PN, JL, and KM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Chung Mau Lo or Kwan Man.

Ethics declarations

Conflict of interest

Kevin Tak-Pan Ng, Jiang Liu, Oscar Wai-Ho Yeung, Li Pang, Hoi Chung Shiu, Hui Liu, Xin Xiang Yang, Albert Chi-Yan Chan, Tiffany Cho-Lam Wong, Chung Mau Lo, Kwan Man declare no conflict of interest.

Ethical approval

The use of clinical samples for research purposes was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA/HKW IRB).

Consent to participate

All patients gave written informed consent.

Consent for publication

All authors approved the manuscript for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 842 KB)

Supplementary file2 (DOCX 46 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ng, K.TP., Liu, J., Yeung, O.WH. et al. Post-transplant inflammatory cytokine signature adds value for predicting tumor recurrence after liver transplantation for hepatocellular carcinoma. Hepatol Int 17, 1596–1609 (2023). https://doi.org/10.1007/s12072-023-10566-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-023-10566-1

Keywords

Search

Navigation