Dataset Information

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

ABSTRACT:

Background and aims

HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear.

Approach and results

We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αβ T cells at both the bulk-cell and single-cell levels in 54 patients with HCC. We deeply investigated HBV-specific T cells and HBV-related T-cell subsets that specifically responded to HBV antigens and the HBV + tumor microenvironment, respectively, characterizing their T-cell receptor clonality and specificity and performing epigenomic profiling. A shared program comprising NFKB1/2-, Proto-Oncogene, NF-KB Sub unit, NFATC2-, and NR4A1-associated unique T-cell receptor-downstream core epigenomic and transcriptomic regulome commonly regulated the differentiation of HBV-specific regulatory T-cell (Treg) cells and CD8 + exhausted T cells; this program was also selectively enriched in the HBV-related Treg-CTLA4 and CD8-exhausted T cell-thymocyte selection associated high mobility subsets and drove greater clonal expansion in HBV-related Treg-CTLA4 subset. Overall, 54% of the effector and memory HBV-specific T cells are governed by transcription factor motifs of activator protein 1, NFE2, and BACH1/2, which have been reported to be associated with prolonged patient relapse-free survival. Moreover, HBV-related tumor-infiltrating Tregs correlated with both increased viral titer and poor prognosis in patients.

Conclusions

This study provides insight into the cellular and molecular basis of the epigenomic programs that regulate the differentiation and generation of HBV-related T cells from viral infection and HBV + HCC unique immune exhaustion.

SUBMITTER: You M

PROVIDER: S-EPMC10442105 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

You Maojun M Gao Yanan Y Fu Junliang J Xie Runze R Zhu Zhenyu Z Hong Zhixian Z Meng Lingzhan L Du Shunda S Liu Junliang J Wang Fu-Sheng FS Yang Pengyuan P Chen Liang L

Hepatology (Baltimore, Md.) 20230401 3

<h4>Background and aims</h4>HBV shapes the T-cell immune responses in HBV-related HCC. T cells can be recruited to the nidus, but limited T cells participate specifically in response to the HBV-related tumor microenvironment and HBV antigens. How epigenomic programs regulate T-cell compartments in virus-specific immune processes is unclear.<h4>Approach and results</h4>We developed Ti-ATAC-seq. 2 to map the T-cell receptor repertoire, epigenomic, and transcriptomic landscape of αβ T cells at both ...[more]

PMID: 36999652

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Project description:Background & aimsConflicting data exist regarding optimal prophylaxis for HBV recurrence (HBV-R) after liver transplantation (LT), particularly in patients with hepatocellular carcinoma (HCC). We assessed current practices for HBV-R prophylaxis in Italy, evaluating rates, risk factors, and the clinical impact of HBV-R and HCC-R.MethodsWe performed a multicentric, retrospective study involving 20 Italian LT centers. All patients who underwent LT for HBV-related liver diseases between 2010 and 2021 were included. Logistic regression was used to identify predictors of HBV-R and HCC-R. Survival curves were estimated with the Kaplan-Meier method and compared with the log-rank test.ResultsWe included 1,205 LT recipients (60.8% with HCC). HBV prophylaxis was prescribed in 99.7% of recipients, mostly with lifelong hepatitis B immunoglobulin+nucleos(t)ide analogues (HBIG+NUCs) (83.9%). Rates of HBV-R were 2.1% and 3.1% in patients transplanted without and with HCC, respectively. Median times from LT were 60 [9.5-77.5] and 5.5 [1-13] months, respectively. Recipients on lifelong HBIG+NUCs experienced lower rates of HBV-R than those in whom HBIG was withdrawn, used only during LT, or in those who received NUCs alone (2.3% vs. 6.2% vs. 1.9% vs. 8%, respectively; p = 0.042). In recipients with HCC, HCC-R rate was 10.8% (median time from LT: 18 months). At multivariate analysis, HBV-R (odds ratio [OR] 10.329; 95% CI 3.665-29.110), Child-Pugh C (OR 3.519; 95% CI 1.305-9.484), and microvascular invasion (OR 3.088; 95% CI 1.692-5.634) were independently associated with HCC-R. Five-year survival was lower in recipients who experienced HCC-R (32.5% vs. 92.4% in those who did not; p <0.001).ConclusionIn Italy, HBV prophylaxis is mostly based on lifelong HBIG+NUCs. HBV-R was rare and not associated with survival in patients transplanted for decompensated cirrhosis. In patients transplanted for HCC, HBV-R was independently associated with HCC-R. The clinical implications of these findings deserve further investigation.Impact and implicationsIn Italy, the combination of high-barrier nucleos(t)ide analogues and hepatitis B immunoglobulins remains the most widely used regimen for antiviral prophylaxis following liver transplantation for HBV-related liver disease. Hepatitis B recurrence after liver transplantation is a rare event and not associated with reduced survival. In transplant recipients with hepatocellular carcinoma, HBV recurrence was independently associated with hepatocellular carcinoma recurrence, though this may simply reflect an epiphenomenon without any causal relationship.

Project description:ImportanceTenofovir disoproxil and entecavir are both commonly used first-line antiviral treatments, but their comparative recurrence and overall survival (OS) benefits remain unclear.ObjectiveTo explore differences of tenofovir disoproxil vs entecavir in recurrence-free survival (RFS) and OS after liver resection with curative intent in patients with hepatocellular cancer (HCC) related to hepatitis B virus (HBV).Design, setting, and participantsThis retrospective cohort study was conducted at Eastern Hepatobiliary Surgery Hospital, a tertiary referral hospital in Shanghai, China, between January 4, 2015, and April 1, 2023. Participants included patients with HBV-related HCC who underwent liver resection with curative intent from January 2015 to December 2018. Patients who received tenofovir disoproxil were matched with patients who received entecavir in a 1:1 ratio using propensity score matching. Data were analyzed from April 3 to May 31, 2023.ExposuresReceiving tenofovir disoproxil or entecavir as antiviral treatment for HBV.Main outcomes and measuresPrimary end points were RFS and OS rates.ResultsAmong 4451 patients (mean [SD] age, 58.1 [10.0] years; 3764 male [84.6%]; median [range] follow-up, of 51 [3 to 91] months), 989 patients in each of the groups were selected in propensity score matching. Baseline characteristics were comparable. In propensity score-matched groups, OS rates were 92.2% at 1 year, 70.9% at 3 years, and 54.2% at 5 years in the entecavir group, compared with 90.9% at 1 year, 75.2% at 3 years, and 64.0% at 5 years in the tenofovir disoproxil group. RFS rates were 83.9% at 1 year, 50.0% at 3 years, and 43.3% at 5 years in the entecavir group, compared with 85.3% at 1 year, 55.6% at 3 years, and 51.4% at 5 years in the tenofovir disoproxil group. Patients in the tenofovir disoproxil group had better OS (hazard ratio, 0.82; 95% CI, 0.72 to 0.94; P = .004) and RFS rates (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = .001) compared with the entecavir group. Restricted mean survival time differences of entecavir vs tenofovir disoproxil groups were -0.05 (95% CI, -0.18 to 0.08) months at 1 year (P = .45), 0.20 (95% CI, -0.62 to 1.03) months at 3 years (P = .63), and 1.82 (95% CI, 0.14 to 3.51) months at 5 years (P = .03).Conclusions and relevanceThese findings suggest that in patients undergoing curative liver resection for HBV-related HCC, tenofovir disoproxil was associated with better long-term OS and RFS rates compared with entecavir, providing insights for antiviral treatment.

Dataset Information

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

Background and aims

Approach and results

Conclusions

Publications

Epigenetic regulation of HBV-specific tumor-infiltrating T cells in HBV-related HCC.

Similar Datasets

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