Abstract 1687: Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma

2020 ◽  
Author(s):  
Man Hsin Hung ◽  
Joo Sang Lee ◽  
Sophia Heinrich ◽  
Ching Wen Chan ◽  
Lichun Ma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
T Cell Exhaustion ◽  
Methionine Metabolism ◽  
Cell Exhaustion

scholarly journals Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Man Hsin Hung ◽  
Joo Sang Lee ◽  
Chi Ma ◽  
Laurence P. Diggs ◽  
Sophia Heinrich ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Therapeutic Strategy ◽  
T Cell Exhaustion ◽  
Methionine Metabolism ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
Integrative Omics

AbstractT-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.

T cell exhaustion dynamics are linked to clinical outcomes in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
M Treiber ◽  
Z Zhang ◽  
H Salié ◽  
C Tauber ◽  
P Otto-Mora ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Clinical Outcomes ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Yu-Tzu Liu ◽  
Tai-Chung Tseng ◽  
Ruey-Shyang Soong ◽  
Chun-Yi Peng ◽  
Yu-Hsing Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals DHX37 Impacts Prognosis of Hepatocellular Carcinoma and Lung Adenocarcinoma through Immune Infiltration

2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Yanni Xu ◽  
Qiongchao Jiang ◽  
Hejun Liu ◽  
Xiaoyun Xiao ◽  
Dinghong Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Lung Adenocarcinoma ◽  
Immune Tolerance ◽  
Prognostic Value ◽  
Complex Function ◽  
T Cell Exhaustion ◽  
Rna Helicases ◽  
Cell Exhaustion

Background. RNA helicases have various essential functions in basically all aspects of RNA metabolism, not only unwinding RNA but also disturbing the interaction of RNA with proteins. Recently, RNA helicases have been considered potential targets in cancers. So far, there has been no detailed investigation of the biological functions of RNA helicase DHX37 in cancers. Objective. We aim to identify the prognostic value of DHX37 associated with tumor microenvironments in cancers. Methods. DHX37 expression was examined via the Oncomine database and Tumor Immune Estimation Resource (TIMER). We explored the prognostic role of DHX37 in cancers across various databases. Coexpression genes, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and fundamental regulators were performed via LinkedOmics. Confirming the prognostic value of DHX37 in liver hepatocellular carcinoma (LIHC) and lung adenocarcinoma (LUAD), we explored the role of DHX37 in infiltrated lymphocytes in cancers using the Gene Expression Profiling Interactive Analysis (GEPIA) and TIMER databases. Results. Through GO and KEGG analyses, expression of DHX37 was also correlated with complex function-specific networks involving the ribosome and RNA metabolic signaling pathways. In LIHC and LUAD, DHX37 expression showed significant positive correlations with markers of Tregs, myeloid-derived suppressor cells (MDSCs), and T cell exhaustion, contributing to immune tolerance. Conclusion. These results indicate that DHX37 can serve as a prognostic biomarker in LIHC and LUAD while having an important role in immune tolerance by activating the function of Tregs, MDSC, and T cell exhaustion.

T cell exhaustion dynamics are linked to clinical outcomes in hepatocellular carcinoma

2020 ◽  
Vol 73 ◽  
pp. S630-S631
Author(s):  
Zhen Zhang ◽  
Catrin Tauber ◽  
Moritz Hess ◽  
Sasikanth Manne ◽  
Annette Schmitt-Gräff ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Clinical Outcomes ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

scholarly journals Genetic and phenotypic difference in CD8+ T cell exhaustion between chronic hepatitis B infection and hepatocellular carcinoma

2018 ◽  
Vol 56 (1) ◽  
pp. 18-21 ◽  
Author(s):  
Xiaochen Wang ◽  
Qifeng He ◽  
Haiyuan Shen ◽  
Xiao-Jie Lu ◽  
Beicheng Sun
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Chronic Hepatitis ◽  
T Cell ◽  
Cell Activity ◽  
T Cell Exhaustion ◽  
Phenotypic Difference ◽  
Cell Exhaustion ◽  
Functional States ◽  
Effector Cytokines

BackgroundSeveral recent studies published have suggested that T cell exhaustion exists both in chronic infection and cancer. However, to date, few studies have investigated their differences. Here we designed this study to explore the genetic and phenotypic difference in CD8+ T cell exhaustion between chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC).MethodsIn this study, we assayed the phenotypes and functional states of CD8+ T cells separating from human CHB tissues and HCC tissues, and re-analyse the single-cell sequencing data (GSE98638) published previously. Clustering analysis of genes was performed using the T cell exhaustion gene modules (modules 1–4) proposed by Speiseret al.ResultsCD8+ T cells from liver tissues of both CHB and HCC showed high levels of exhaustion markers, DOI: programmed cell death-1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3), decreased proliferation (Ki67) and cell activity (CD69), and reduced production of effector cytokines (interferon-γ, interleukin-2 and tumour necrosis factor-α). Compared with CD8+ T cells from CHB tissues, those from HCC tissue showed higher expression levels of exhaustion markers, lower levels of proliferation, cell activity and the production of effector cytokines. Cluster analysis showed that exhaustion associated genes in CHB and HCC are inclined to distribute into modules 3 while those isolated from HCC into modules 1 and 2.ConclusionsCD8+ T cell exhaustion existed both in CHB and HCC, but the phenotypes, functional states and underlying mechanisms are somewhat different between the two.

scholarly journals AGTRAP Is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shanshan Liu ◽  
Wei Zhao ◽  
Xuemei Li ◽  
La Zhang ◽  
Yu Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Normal Liver ◽  
Mrna Levels ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration ◽  
Protein Levels ◽  
Liver Tissues

BackgroundRecently, it has been reported that angiotensin II receptor-associated protein (AGTRAP) plays a substantial role in tumor progression. Nevertheless, the possible role of AGTRAP in hepatocellular carcinoma (HCC) remains unrecognized.MethodsThe metabolic gene rapid visualizer, Cancer Cell Line Encyclopedia, Human Protein Atlas, and Hepatocellular Carcinoma Database were used to analyze the expression of AGTRAP in HCC tissues and normal liver tissues or adjacent tissues. Kaplan-Meier plotter and UALCAN analysis were used to assess the prognostic and diagnostic value of AGTRAP. LinkedOmics and cBioPortal were used to explore the genes co-expressed with AGTRAP in HCC. To further understand the potential mechanism of AGTRAP in HCC, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were performed using R software, the protein-protein interaction (PPI) network was established using the STRING database, and the immune infiltration and T-cell exhaustion related to AGTRAP were explored via Timer and GEPIA. In addition, immunohistochemistry was used to detect the expression of AGTRAP protein in HCC tissues and paired adjacent tissues from clinical specimens.ResultsThis study found that the mRNA and protein levels of AGTRAP in HCC tissues were higher than those in normal liver tissues and adjacent tissues, and higher mRNA levels of AGTRAP were associated with higher histological grade and a poor overall survival in HCC patients. The area under the receiver operating characteristic curve (AUC) of AGTRAP was 0.856, suggesting that it could be a diagnostic marker for HCC. Moreover, the alteration rate of AGTRAP in HCC was 8%, and AGTRAP was involved in HCC probably through the NF-κB and MAPK signaling pathways. Furthermore, AGTRAP was positively correlated with the infiltration of CD8+ T cells, CD4+ T cells, B cells, macrophages, dendritic cells, and neutrophils, and the levels of AGTRAP were significantly correlated with T-cell exhaustion biomarkers. The immunohistochemistry results confirmed that the protein levels of AGTRAP were consistently higher in HCC tissues than in paired adjacent tissues.ConclusionThe clinical value of AGTRAP and its correlation with immune infiltration in HCC was effectively identified in clinical data from multiple recognized databases. These findings indicate that AGTRAP could serve as a potential biomarker in the treatment of HCC, thereby informing its prognosis, diagnosis, and even immunotherapy.

scholarly journals Exploring Markers of Exhausted CD8 T Cells to Predict Response to Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma

Liver Cancer ◽  
2021 ◽  
pp. 1-14
Author(s):  
Chia-Lang Hsu ◽  
Da-Liang Ou ◽  
Li-Yuan Bai ◽  
Chia-Wei Chen ◽  
Li Lin ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

<b><i>Background:</i></b> Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. <b><i>Objectives:</i></b> The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). <b><i>Methods:</i></b> Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. <b><i>Results:</i></b> HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (<i>n</i> = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8<sup>+</sup>LAG3<sup>+</sup> cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (<i>n</i> = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. <b><i>Conclusions:</i></b> CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.

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