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
Data Availability
Data generated or analyzed during this study are available from the corresponding author on reasonable request.
References
Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380(15):1450–1462
Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017;14(4):203–217
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
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
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
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
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
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
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
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
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
Liu J, Lo CM, Man K. Role of intrahepatic regional immunity in post-transplant cancer recurrence. Engineering. 2022;10:57–64
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
Akamatsu N, Kokudo N. Liver transplantation for hepatocellular carcinoma from living-donor vs. deceased donor. Hepatobiliary Surg Nutr. 2016;5(5):422–428
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
Man K. Recurrent malignancy: are we pushing the envelope? Liver Transpl. 2017;23(S1):S81–S84
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
Refolo MG, Messa C, Guerra V, Carr BI, D’Alessandro R. Inflammatory mechanisms of HCC development. Cancers (Basel). 2020;12(3):641
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
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
Hwang W, Lee J. Pathophysiologic Implications of cytokines secretion during liver transplantation surgery. Int J Med Sci. 2018;15(14):1737–1745
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
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
Heinze G, Dunkler D. Five myths about variable selection. Transpl Int. 2017;30(1):6–10
Toniutto PFE, Fumolo E, Bitetto D. Risk factors for hepatocellular carcinoma recurrence after liver transplantation. Hepatoma Res. 2020;6:50
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
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
Shih KC, Man K. Small-for-size liver graft injury–impact on tumor behavior. Transplant Rev (Orlando). 2010;24(1):1–10
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
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
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
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
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
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
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
Agarwal PD, Lucey MR. Management of hepatocellular carcinoma recurrence after liver transplantation. Ann Hepatol. 2022;27(1):100654
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
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
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.
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
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
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
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
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
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
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.
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.
About this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12072-023-10566-1