Decoding Epigenetic Mechanisms Driving Immune Evasion in Liver Cancer With Omics Approaches (DELIVER)

This is a national, observational, retrospective, cross-sectional, non-profit study focused on patients with HCC. The study aims to characterize the expression and function of novel noncoding regulatory transcripts, including those containing TEsin the microenvironment of liver tumors, with emphasis on their role in T cell dysfunction.

Study Overview

• Status: Recruiting
• Conditions: Hepatocarcinoma
• Intervention / Treatment: Genetic: Collection of tumor tissue (Fresh or/and archival FFPE), blood samples

Detailed Description

We will use TILs, along with other immune, hepatocyte, and stromal cell populations isolated from hepatocellular carcinoma (HCC) tissue, matched adjacent non-tumoral liver, and peripheral blood samples. Single-cell RNA sequencing and spatial transcriptomics will be employed to define the cellular distribution and molecular profiles of TE-containing transcripts, other noncoding RNAs, and associated gene expression programs within the HCC microenvironment. Functional experiments-including CRISPR-Cas13 or ASO-mediated silencing-will be performed to elucidate the role of the novel regulatory transcripts, including TE-transcripts, in modulating cellular identity within the liver TME. In parallel, epigenetic analyses such as ChIPseq, ATAC-seq, DNA methylation profiling, RADICL-seq, and Hi-C will be conducted to map the regulatory networks and chromatin architecture associated with these transcripts

• Study Type: Observational
• Enrollment (Estimated): 270

Contacts and Locations

• Study Contact: Name: Gianluca Mauri, MD; Phone Number: 3695 +39026444; Email: gianluca.mauri@ospedaleniguarda.it

Study Locations

• Italy
  • Lombardy
    • Milan, Lombardy, Italy, 20162
      • Recruiting
      • ASST GOM Niguarda
      • Contact: Gianluca Mauri, MD; Phone Number: 3695 +39026444; Email: gianluca.mauri@ospedaleniguarda.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with HCC and eligible for biopsy or surgical resection

Description

1. Histological/radiological (LR-4 o 5)diagnosis of hepatocellular carcinoma (HCC).
2. Solid tumor fresh tissue availability from HCC biospy or surgical resectionas per standard clinical practice, and/orHCC FFPE archival samples availability.
3. Capability of understanding and signing an inform consent form.
4. Known hepatits B and C status, including HBeAg (positive or negative), viral load (HBVDNA e HCV-RNA), HCV genotype, whether sustained virological response (SVR)was obtainedand potential antiviral treatments received (including direct antiretroviral therapy(DAA)and interferon). These parameters will be exploited to stratify patients and analyze the impact of the virological status on microenvironmental immunological features, with particular regards to immunesuppression mechanisms.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HCC patients; 120 patients will be prospectively recruitedand from whom fresh tumor samples and blood samples will be collected. 150 HCC patients treated by surgery FFPE samples will be retrospectively collected	Genetic: Collection of tumor tissue (Fresh or/and archival FFPE), blood samples; NGS, immunofluorescence analyses, transcriptional and immunophenotypic analyzes, scRNAseq, ChIP-seq/ATAC-seq, DNA methylation, single-cell transcriptomic and TCR sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize the molecular mechanisms underlying T cell dysfunction	To characterize the molecular mechanisms underlying T cell dysfunction and immune evasion in the tumor microenvironment of hepatocellular carcinoma, through the identification and functional definition of novel non-coding regulatory transcripts - including those containing transposable elements - expressed at single-cell resolution. Identification of TE-containing transcripts expressed in tumor-infiltrating lymphocytes (TILs) and other cellular populations within the HCC tumor microenvironment, using single-cell transcriptomics (scRNA-seq) and spatial transcriptomics technologies.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Analyze the epigenetic transcriptional regulatory mechanisms	To analyze the epigenetic and transcriptional regulatory mechanisms mediated by the newly identified transcripts from the primary objective, including TEcontaining transcripts, in the cellular components of the HCC tumor microenvironment. Mapping of the genomic occupancy, epigenetic landscape, and three-dimensional chromatin conformation associated with the newly identified regulatory transcripts, including those containing TEs, in TME cells, with particular attention to TILs.	5 years
Retrospective analysis on FFPE samples	Evaluation of the expression dynamics of regulatory transcripts, including those containing TEs, as potential predictive biomarkers of response to immunotherapy, through retrospective analysis on FFPE tissue samples.	5 years

Collaborators and Investigators

• Sponsor: Niguarda Hospital
• Collaborators: University of Milan; San Raffaele University Hospital, Italy; Fondazione Istituto Nazionale Genetica Molecolare - INGM
• Investigators: Principal Investigator: Gianluca Mauri, MD, ASST Grande Ospedale Metropolitano Niguarda

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Estimated): January 31, 2029
• Study Completion (Estimated): January 31, 2031

Study Registration Dates

• First Submitted: February 19, 2026
• First Submitted That Met QC Criteria: February 19, 2026
• First Posted (Actual): February 25, 2026

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: 6605

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Not yet decided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No