Dataset Information

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

ABSTRACT:

Background and aims

The key role of tissue-resident memory T (T_RM) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on T_RM cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) is a classical ligand of LAG-3 and can promote T cell exhaustion in tumors. Here, we excavated the effect of FGL1-LAG3 regulatory axis on T_RM cells in HCC.

Methods

The function and phenotype of intrahepatic CD8⁺ T_RM cells in 35 HCC patients were analyzed using multicolor flow cytometry. Using a tissue microarray of 80 HCC patients, we performed the prognosis analysis. Moreover, we investigated the suppressive effect of FGL1 on CD8⁺ T_RM cells both in in vitro induction model and in vivo orthotopic HCC mouse model.

Results

There was an increase in LAG3 expression in CD8⁺ T_RM cells in end-stage HCC; moreover, FGL1 levels were negatively correlated with CD103 expression and related to poor outcomes in HCC. Patients with high CD8⁺ T_RM cell proportions have better outcomes, and FGL1-LAG3 binding could lead to the exhaustion of CD8⁺ T_RM cells in tumors, indicating its potential as a target for immune checkpoint therapy of HCC. Increased FGL1 expression in HCC may result in CD8⁺ T_RM cell exhaustion, causing tumor immune escape.

Conclusions

We identified CD8⁺T_RM cells as a potential immunotherapeutic target and reported the effect of FGL1-LAG3 binding on CD8⁺ T_RM cell function in HCC.

SUBMITTER: Yang C

PROVIDER: S-EPMC10040674 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

Yang Changjie C Qian Qiwei Q Zhao Yudong Y Huang Bingyuan B Chen Ruilin R Gong Qiyu Q Ji Hao H Wang Chenchen C Xia Lei L You Zhengrui Z Zhang Jianjun J Chen Xiaosong X

Frontiers in immunology 20230313

<h4>Background and aims</h4>The key role of tissue-resident memory T (T<sub>RM</sub>) cells in the immune regulation of hepatocellular carcinoma (HCC) has been investigated and reported, but the regulatory mechanism of tumor microenvironment on T<sub>RM</sub> cells is still unclear. Lymphocyte activating gene 3 (LAG-3) is a promising next-generation immune checkpoint that is continuously expressed due to persistent antigen exposure in the tumor microenvironment. Fibrinogen-like protein 1 (FGL1) ...[more]

PMID: 36993960

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Project description:BackgroundAdenosine monophosphate-activated protein kinase (AMPK) is associated with the development of liver hepatocellular carcinoma (LIHC). AMPKα2, an α2 subunit of AMPK, is encoded by PRKAA2, and functions as the catalytic core of AMPK. However, the role of AMPKα2 in the LIHC tumor immune environment is unclear.MethodsRNA-seq data were obtained from the Cancer Genome Atlas and Genotype-Tissue Expression databases. Using the single-cell RNA-sequencing dataset for LIHC obtained from the China National Genebank Database, the communication between malignant cells and T cells in response to different PRKAA2 expression patterns was evaluated. In addition, the association between PRKAA2 expression and T-cell evolution during tumor progression was explored using Pseudotime analysis, and the role of PRKAA2 in metabolic reprogramming was explored using the R "scMetabolis" package. Functional experiments were performed in LIHC HepG2 cells.ResultsAMPK subunits were expressed in tissue-specific and substrate-specific patterns. PRKAA2 was highly expressed in LIHC tissues and was associated with poor patient prognosis. Tumors with high PRKAA2 expression displayed an immune cold phenotype. High PRKAA2 expression significantly promoted LIHC immune escape. This result is supported by the following evidence: 1) the inhibition of major histocompatibility complex class I (MHC-I) expression through the regulation of interferon-gamma activity in malignant cells; 2) the promotion of CD8+ T-cell exhaustion and the formation of CD4+ Treg cells in T cells; 3) altered interactions between malignant cells and T cells in the tumor immune environment; and 4) induction of metabolic reprogramming in malignant cells.ConclusionsOur study indicate that PRKAA2 may contribute to LIHC progression by promoting metabolic reprogramming and tumor immune escape through theoretical analysis, which offers a theoretical foundation for developing PRKAA2-based strategies for personalized LIHC treatment.

Project description:IntroductionDespite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3+ T cells and monocytes. However, its specific role in the HCC TME remains unclear.MethodsIn this current study, we used cytometry time-of-flight (CyTOF), bulk RNA sequencing on sorted T cells, and single-cell RNA (scRNA) sequencing to interrogate expression of CD38 and its correlation with T cell exhaustion in HCC samples. We also employed multiplex immunohistochemistry (mIHC) for validating our findings.ResultsFrom CyTOF analysis, we compared the immune composition of CD38-expressing leukocytes in TILs, non-tumor tissue-infiltrating leukocytes (NIL), and peripheral blood mononuclear cells (PBMC). We identified CD8+ T cells as the dominant CD38-expressing TILs and found that CD38 expression was significantly higher in CD8+ TRM in TILs than in NILs. Furthermore, through transcriptomic analysis on sorted CD8+ TRM from HCC tumors, we observed a higher expression of CD38 along with T cell exhaustion genes, including PDCD1 and CTLA4, compared to the circulating memory CD8 T cells from PBMC. This was validated by scRNA sequencing that revealed co-expression of CD38 with PDCD1, CTLA4, and ITGAE (CD103) in T cells from HCC tumors. The protein co-expression of CD38 and PD-1 on CD8+ T cells was further demonstrated by mIHC on HCC FFPE tissues, marking CD38 as a T cell co-exhaustion marker in HCC. Lastly, the higher proportions of CD38+PD-1+ CD8+ T cells and CD38+PD-1+ TRM were significantly associated with the higher histopathological grades of HCC, indicating its role in the aggressiveness of the disease.ConclusionTaken together, the concurrent expression of CD38 with exhaustion markers on CD8+ TRM underpins its role as a key marker of T cell exhaustion and a potential therapeutic target for restoring cytotoxic T cell function in HCC.

Dataset Information

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

Background and aims

Methods

Results

Conclusions

Publications

Fibrinogen-like protein 1 promotes liver-resident memory T-cell exhaustion in hepatocellular carcinoma.

Similar Datasets

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