Abstract 7035: Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics

Abstract As the fifth leading cause of cancer-related mortality, liver cancer imposes a global burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with a five-year overall survival rate of less than 20% for advanced-stage cases. Even the most advanced immunotherapy for HCC has disparate response rates in each patient with HCC, which has led to efforts to unravel the underlying factors in the progression of HCC using bioinformatic approaches. In recent decades, numerous studies have explored T-cell subtypes with tissue-specific residency, suggesting their early protective functions and therapeutic potential within tumor microenvironment (TME). This study aimed to understand inter-individual and intercellular TME through single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) in five recurrent/non-recurrent HCC patients. We identified tumor-associated tissue-resident memory T (TA-TRM) cells and investigated the heterogeneous characteristics of two TRM clusters (CD69+ and CD103+). Whereas CD69+ TA-TRM showed high expression of genes associated with immunological activation, CD103+ TA-TRM exhibited upregulation of genes related to proliferation capacity. To validate the unique molecular patterns, we analyzed an independent HCC dataset (GSE140228) and observed high concordance of significant core marker genes for TA-TRM clusters between the two datasets. Moreover, we assessed the association of gene expression in TA-TRM cells with overall and recurrence-free survival by conducting survival analysis in two independent large-scale cohorts. The cross-validation approach was applied to estimate risk scores for patients with primary HCC tumors in The Cancer Genome Atlas (TCGA), and the trained model was evaluated using the International Cancer Genome Consortium (ICGC) data. The result of calculating the risk scores clearly indicates that TA-TRM cells are associated with survival in HCC. Therefore, our study characterized two distinct subtypes of TA-TRM cells in HCC, delineated their unique molecular signatures, and established their relevance to survival outcomes. The findings can potentially enhance the understanding of the roles of TA-TRM cells in the context of HCC. Citation Format: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won. Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7035.