Immunological and Molecular Correlates of Disease Recurrence After Liver Resection for Hepatocellular Carcinoma

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2012 Mar 8

PMID 22396772

Citations 41

Authors

Elisabetta Cariani

Massimo Pilli

Alessandro Zerbini

Cristina Rota

Andrea Olivani

Guido Pelosi

Claudia Schianchi

Paolo Soliani

Nicoletta Campanini

Enrico Maria Silini

Tommaso Trenti

Carlo Ferrari

Gabriele Missale

Affiliations

Soon will be listed here.

Abstract

The definition of the risk of hepatocellular carcinoma (HCC) recurrence after resection represents a central issue to improve the clinical management of patients. In this study we examined the prognostic relevance of infiltrating immune cell subsets in the tumor (TIL) and in nontumorous (NT) liver (LIL), and the expression of immune-related and lineage-specific mRNAs in HCC and NT liver derived from 42 patients. The phenotype of infiltrating cells was analyzed by flow cytometry, and mRNA expression in liver tissue was examined by real-time reverse transcription (RT)-PCR. The tumor immune microenvironment was enriched in inhibitory and dysfunctional cell subsets. Enrichment in CD4+ T-cells and in particular CD4 and CD8+ memory subsets within TIL was predictive of better overall survival (OS) and time to recurrence (TTR). Increased programmed death ligand 1 (PDL1) mRNA content and higher prevalence of invariant NKT (iNKT) cells were associated with shorter OS and TTR, respectively. By combined evaluation of infiltrating cell subsets along with mRNA profiling of immune and tumor related genes, we identified the intratumoral frequency of memory T-cells and iNKT-cells as well as PDL1 expression as the best predictors of clinical outcome. HCC infiltrate is characterized by the expression of molecules with negative regulatory function that may favor tumor recurrence and poor survival.

Citing Articles

Drugs and drug targets for the treatment of HPV-positive cervical cancer.

Burmeister C, Khan S, Prince S Tumour Virus Res. 2024; 19():200309.

PMID: 39709045 PMC: 11733058. DOI: 10.1016/j.tvr.2024.200309.

JDF promotes the apoptosis of M2 macrophages and reduces epithelial-mesenchymal transition and migration of liver cancer cells by inhibiting CSF-1/PI3K/AKT signaling pathway.

Liu X, Wang Z, Lv X, Tao Z, Lin L, Zhao S Heliyon. 2024; 10(15):e34968.

PMID: 39170340 PMC: 11336322. DOI: 10.1016/j.heliyon.2024.e34968.

Impact of inflammation and the immune system on hepatocellular carcinoma recurrence after hepatectomy.

She S, Shi J, Zhu J, Yang F, Yu J, Dai K Cancer Med. 2024; 13(4):e7018.

PMID: 38457189 PMC: 10922023. DOI: 10.1002/cam4.7018.

Decoding Immune Signature to Detect the Risk for Early-Stage HCC Recurrence.

Devan A, Nair B, Aryan M, Liju V, Koshy J, Mathew B Cancers (Basel). 2023; 15(10).

PMID: 37345066 PMC: 10216348. DOI: 10.3390/cancers15102729.

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope.

Jia W, Zhang T, Yao Q, Li J, Nie Y, Lei X Front Immunol. 2022; 13:870458.

PMID: 35844587 PMC: 9278517. DOI: 10.3389/fimmu.2022.870458.

References

Kobayashi N, Hiraoka N, Yamagami W, Ojima H, Kanai Y, Kosuge T . FOXP3+ regulatory T cells affect the development and progression of hepatocarcinogenesis. Clin Cancer Res. 2007; 13(3):902-11. DOI: 10.1158/1078-0432.CCR-06-2363. View

Villanueva A, Hoshida Y, Toffanin S, Lachenmayer A, Alsinet C, Savic R . New strategies in hepatocellular carcinoma: genomic prognostic markers. Clin Cancer Res. 2010; 16(19):4688-94. PMC: 3395071. DOI: 10.1158/1078-0432.CCR-09-1811. View

Gao Q, Wang X, Qiu S, Yamato I, Sho M, Nakajima Y . Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15(3):971-9. DOI: 10.1158/1078-0432.CCR-08-1608. View

Lee J, Heo J, Libbrecht L, Chu I, Kaposi-Novak P, Calvisi D . A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006; 12(4):410-6. DOI: 10.1038/nm1377. View

Breuhahn K, Vreden S, Haddad R, Beckebaum S, Stippel D, Flemming P . Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression. Cancer Res. 2004; 64(17):6058-64. DOI: 10.1158/0008-5472.CAN-04-0292. View

Gao Q, Qiu S, Fan J, Zhou J, Wang X, Xiao Y . Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007; 25(18):2586-93. DOI: 10.1200/JCO.2006.09.4565. View

Hoshida Y, Nijman S, Kobayashi M, Chan J, Brunet J, Chiang D . Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009; 69(18):7385-92. PMC: 3549578. DOI: 10.1158/0008-5472.CAN-09-1089. View

Disis M . Immune regulation of cancer. J Clin Oncol. 2010; 28(29):4531-8. PMC: 3041789. DOI: 10.1200/JCO.2009.27.2146. View

Zhou J, Ding T, Pan W, Zhu L, Li L, Zheng L . Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009; 125(7):1640-8. DOI: 10.1002/ijc.24556. View

10.

El-Serag H, Rudolph K . Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007; 132(7):2557-76. DOI: 10.1053/j.gastro.2007.04.061. View

11.

Yamashita T, Forgues M, Wang W, Kim J, Ye Q, Jia H . EpCAM and alpha-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res. 2008; 68(5):1451-61. DOI: 10.1158/0008-5472.CAN-07-6013. View

12.

Unitt E, Marshall A, Gelson W, Rushbrook S, Davies S, Vowler S . Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol. 2006; 45(2):246-53. DOI: 10.1016/j.jhep.2005.12.027. View

13.

Mareel M, Leroy A . Clinical, cellular, and molecular aspects of cancer invasion. Physiol Rev. 2003; 83(2):337-76. DOI: 10.1152/physrev.00024.2002. View

14.

Yang X, Yamagiwa S, Ichida T, Matsuda Y, Sugahara S, Watanabe H . Increase of CD4+ CD25+ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol. 2006; 45(2):254-62. DOI: 10.1016/j.jhep.2006.01.036. View

15.

Lee J, Chu I, Heo J, Calvisi D, Sun Z, Roskams T . Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004; 40(3):667-76. DOI: 10.1002/hep.20375. View

16.

Shi F, Shi M, Zeng Z, Qi R, Liu Z, Zhang J . PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer. 2010; 128(4):887-96. DOI: 10.1002/ijc.25397. View

17.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C . Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006; 313(5795):1960-4. DOI: 10.1126/science.1129139. View

18.

Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M . Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 1998; 27(2):407-14. DOI: 10.1002/hep.510270214. View

19.

Boyault S, Rickman D, De Reynies A, Balabaud C, Rebouissou S, Jeannot E . Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2006; 45(1):42-52. DOI: 10.1002/hep.21467. View

20.

Chew V, Tow C, Teo M, Wong H, Chan J, Gehring A . Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol. 2009; 52(3):370-9. DOI: 10.1016/j.jhep.2009.07.013. View