Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B

Gao, Yanan; You, Maojun; Fu, Junliang; Tian, Meijie; Zhong, Xianqiong; Du, Chengzhi; Hong, Zhixian; Zhu, Zhenyu; Liu, Junliang; Markowitz, Geoffrey J.; Wang, Fusheng; Yang, Pengyuan

doi:10.1016/j.jhep.2021.08.029

Cited by 96 publications

(67 citation statements)

References 27 publications

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“…Tregs, one subset of T lymphocytes that regulate the immune response according to suppressing the effector T lymphocytes ( 39 , 40 ). Tregs have been shown to promote tumor development, for example, in non-alcoholic steatohepatitis (NASH) -associated HCC, Tregs interact with neutrophil extracellular traps (NETs) to inhibit immune surveillance to exert oncogenic effects in the early stage of NASH, while in HBV-associated HCC, specifically blocking the infiltration of Tregs could enhance the anti-tumor immunity and Tregs expression correlated with sorafenib resistance and HBV load titers ( 41 , 42 ). In cancer, the differentiation of myeloid cells is often altered, producing a cohort of immature myeloid cells called MDSCs that have strong immunosuppressive activity and impaired function as antigen-presenting cells (APCs) ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment

Zhang

Ding

et al. 2022

Front. Oncol.

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Hepatocellular carcinoma (HCC) is one of the deadliest tumors in the world and is notorious for poor prognosis. There is mounting evidence that pseudouridine performs key functions in the initiation and progression of several cancers. A previous study demonstrated that Pseudouridine 5’-phosphatase (PUDP) may be a novel prognostic biomarker in colorectal cancer. However, in the past, we have paid little attention to PUDP and we are still not clear about its function and role in cancer. In this study, a pan-cancer analysis of PUDP expression and prognosis was performed firstly using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) data and we found that PUDP may be a potential oncogene for HCC. Then the most potential upstream microRNA contributing to PUDP was identified as let-7c-5p through expression analysis, correlation analysis, and survival analysis. Subsequently, the result of single cell RNA sequencing (scRNA-seq) demonstrated that PUDP was significantly highly expressed on malignant cells. In addition, there are significantly positive correlations between PUDP and tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression, especially with tumor-promoting immune cells such as T cell regulatory (Treg), Myeloid-derived suppressor cell (MDSC), cancer-associated fibroblast (CAF). Moreover, we found the methylation level of three loci was positively correlated with PUDP expression and four loci were negatively correlated. 15 pairs of HCC and normal adjacent tissues from HCC patients who were treated at our center were used to verify the results of the bioinformatics analysis and the results of experiments are similar to the bioinformatics analysis. Our study demonstrated that HCC patients with high PUDP expression are less likely to benefit from immunotherapy, and in addition, we explored the relationship between PUDP and anticancer drugs. Finally, we explored the clinical relevance of PUDP, identified PUDP as an independent risk factor for HCC patients and constructed a prognostic model, used International Cancer Genome Consortium (ICGC) data to do external validation. Collectively, our study demonstrated that high expression of PUDP suggested a poor prognosis and low response to immunotherapy, providing new insight into the treatment and prognosis of HCC.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment

Zhang

Ding

et al. 2022

Front. Oncol.

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“…A recent study has identified that CCR4 + Tregs (Figure 1 ) are the predominant type of Tregs in HBV + HCC. 160 CCR4 is mainly expressed on Tregs and other T‐helper cells, which can mediate Tregs trafficking into the TME by interacting with its ligands, CCL22 and CCL17. 161 The findings showed that the high frequency of CCR4 + Tregs exhibited potently immunosuppressive stem‐like specificity by upregulating transcription factor 1 (TCF1), PD‐1, and CTLA‐4 levels and secreting more IL‐10 and IL‐35.…”

Section: Treg Subsets In Tumor Immunitymentioning

confidence: 99%

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Jiang

Zhu

Wang

et al. 2022

MedComm

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CD4 + CD25 + regulatory T cells (Tregs), a subpopulation of naturally CD4 + T cells that characteristically express transcription factor Forkhead box P3 (FOXP3), play a pivotal role in the maintenance of immune homeostasis and the prevention of autoimmunity. With the development of biological technology, the understanding of plasticity and stability of Tregs has been further developed. Recent studies have suggested that human Tregs are functionally and phenotypically diverse. The functions and mechanisms of different phenotypes of Tregs in different disease settings, such as tumor microenvironment, autoimmune diseases, and transplantation, have gradually become hot spots of immunology research that arouse extensive attention. Among the complex functions, CD4 + CD25 + FOXP3 + Tregs possess a potent immunosuppressive capacity and can produce various cytokines, such as IL‐2, IL‐10, and TGF‐β, to regulate immune homeostasis. They can alleviate the progression of diseases by resisting inflammatory immune responses, whereas promoting the poor prognosis of diseases by helping cells evade immune surveillance or suppressing effector T cells activity. Therefore, methods for targeting Tregs to regulate their functions in the immune microenvironment, such as depleting them to strengthen tumor immunity or expanding them to treat immunological diseases, need to be developed. Here, we discuss that different subpopulations of Tregs are essential for the development of immunotherapeutic strategies involving Tregs in human diseases.

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“…These tumor-infiltrating lymphocytes (TILs) were suggested to be related to the response of immune checkpoints such as PD-1 and PD-L1 [ 25 , 52 ], so that the efficacy of PD-1/PD-L1 inhibitors may be differed between high- and low-risk patients. Meanwhile, in patients from the high-risk group there was a significantly higher abundance of Tregs indicating the suppressive immunotherapy in HCC as reported before [ 53 ], while tivozanib [ 54 ] and cystathionine β -synthase [ 55 ] could decrease Tregs infiltration. Therefore, the combined treatment of immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors, with the antioxidant drugs and tivozanib or cystathionine β -synthase was highly recommended for the advanced HCC patients with high prognosis score.…”

Section: Discussionmentioning

confidence: 52%

Mitochondrial-Related Transcriptome Feature Correlates with Prognosis, Vascular Invasion, Tumor Microenvironment, and Treatment Response in Hepatocellular Carcinoma

Wang

Song

Zhang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer, which was highly correlated with metabolic dysfunction. Nevertheless, the association between nuclear mitochondrial-related transcriptome and HCC remained unclear. Materials and Methods. A total of 147 nuclear mitochondrial-related genes (NMRGs) were downloaded from the MITOMAP: A Human Mitochondrial Genome Database. The training dataset was downloaded from The Cancer Genome Atlas (TCGA), while validation datasets were retrieved from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). The univariate and multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were applied to construct a NMRG signature, and the value of area under receiver operating characteristic curve (AUC) was utilized to assess the signature and nomogram. Then, data from the Genomics of Drug Sensitivity in Cancer (GDSC) were used for the evaluation of chemotherapy response in HCC. Results. Functional enrichment of differentially expressed genes (DEGs) between HCC and paired normal tissue samples demonstrated that mitochondrial dysfunction was significantly associated with HCC development. Survival analysis showed a total of 35 NMRGs were significantly correlated with overall survival (OS) of HCC, and the LASSO Cox regression analysis further identified a 25-NMRG signature and corresponding prognosis score based on their transcriptional profiling. HCC patients were divided into high- and low-risk groups according to the median prognosis score, and high-risk patients had significantly worse OS (median OS: 27.50 vs. 83.18 months, P < 0.0001 ). The AUC values for OS at 1, 3, and 5 years were 0.79, 0.77, and 0.77, respectively. The prognostic capacity of NMRG signature was verified in the GSE14520 dataset and ICGC-HCC cohort. Besides, the NMRG signature outperformed each NMRG and clinical features in prognosis prediction and could also differentiate whether patients presented with vascular invasions (VIs) or not. Subsequently, a prognostic nomogram (C-index: 0.753, 95% CI: 0.703~0.804) by the integration of age, tumor metastasis, and NMRG prognosis score was constructed with the AUC values for OS at 1, 3, and 5 years were 0.82, 0.81, and 0.82, respectively. Notably, significant enrichment of regulatory and follicular helper T cells in high-risk group indicated the potential treatment of immune checkpoint inhibitors for these patients. Interestingly, the NMRG signature could also identify the potential responders of sorafenib or transcatheter arterial chemoembolization (TACE) treatment. Additionally, HCC patients in high-risk group appeared to be more sensitive to cisplatin, vorinostat, and methotrexate, reversely, patients in low-risk group had significantly higher sensitivity to paclitaxel and bleomycin instead. Conclusions. In summary, the development of NMRG signature provided a more comprehensive understanding of mitochondrial dysfunction in HCC, helped predict prognosis and tumor microenvironment, and provided potential targeted therapies for HCC patients with different NMRG prognosis scores.

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Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B

Cited by 96 publications

References 27 publications

Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment

Bioinformatics Analysis Combined With Experiments Predicts PUDP as a Potential Prognostic Biomarker for Hepatocellular Carcinoma Through Its Interaction With Tumor Microenvironment

Different subpopulations of regulatory T cells in human autoimmune disease, transplantation, and tumor immunity

Mitochondrial-Related Transcriptome Feature Correlates with Prognosis, Vascular Invasion, Tumor Microenvironment, and Treatment Response in Hepatocellular Carcinoma

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