Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma

Dong, Liangqing; Peng, Lihua; Ma, Li; Liu, Dongbing; Zhang, Shu; Luo, Shu-zhen; Rao, Junhua; Zhu, Hongwen; Yang, Shenghong; Xi, Shui-jun; Chen, Min; Xie, Fanfan; Li, Fuqiang; Li, Wenhui; Wang, Hongzhi; Lin, Liya; Wang, Yujue; Wang, Xiaoying; Gao, Daming; Zhou, Hu; Yang, Huanming; Wang, Jian; Zhu, Shida; Wang, Xiangdong; Cao, Yang; Zhou, Jian; Fan, Jia; Wu, Kui; Gao, Qiang

doi:10.1016/j.jhep.2019.12.014

Cited by 146 publications

(113 citation statements)

References 43 publications

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“…(28-30) However, Dong, et al recently showed that in multifocal HCC neo-antigens are unique to every tumor lesion, whereas CTA expression was conserved between lesions. (31). These data indicate that effective therapeutic vaccination with neoantigens in these patients requires analysis of mutations in every lesion and design of a vaccine consisting of neo-antigens expressed in different lesions.…”

Section: Discussionmentioning

confidence: 99%

Expression of Cancer testis Antigens in Tumor-adjacent Normal Liver Predicts Post-resection Recurrence of Hepatocellular Carcinoma

Noordam

Ozturk

et al. 2020

Preprint

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Background: High recurrence rates after resection of hepatocellular cancer (HCC) with curative intent and lack of effective therapy for advanced disease impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims of this study were to establish a panel of CTAs that are frequently and selectively expressed in tumors of HCC-patients, and to investigate whether CTAs might be expressed in tumor-free liver tissues of HCC-patients.Methods: Surgically-resected tumor and paired tumor-free (TFL) tissues of HCC patients (n=100), healthy livers (n=21), and other healthy tissues (n=22 different tissues) were assessed for mRNA expression of 49 carefully selected CTAs by RT-qPCR. Protein expression of 5 CTAs was determined by immunohistochemistry (n=78).Results: Twelve CTAs were expressed at mRNA level in ≥10% of HCC-tumor tissues and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein expression was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA expression in TFL was an independent negative prognostic factor for HCC-recurrence and survival after tumor resection.Conclusions: We established a novel panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients, that can be safely used for immunotherapeutic targeting of HCC. The increased risk of HCC recurrence in patients with CTA expression in TFL suggests that CTA-expressing (pre-)malignant cells may be a source of HCC recurrence. Therefore, immunotherapeutic targeting of these antigens should be considered as adjuvant therapy to prevent HCC-recurrence after tumor resection. Lay summary:Expression of multiple defined cancer testis antigens in non-cancerous liver tissue is associated with significantly increased cancer-recurrence and worse patient survival after tumor resection. We propose that immunotherapeutic targeting of these antigens may prevent HCC recurrence after tumor resection.

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Section: Discussionmentioning

confidence: 99%

Expression of Cancer testis Antigens in Tumor-adjacent Normal Liver Predicts Post-resection Recurrence of Hepatocellular Carcinoma

Noordam

Ozturk

et al. 2020

Preprint

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“…The immune system plays an important role in the tumor microenvironment and plays a vital role in the development, progression, metastasis and recurrence of cancer [32]. Cancer cells and immune cells show metabolic reprogramming in the tumor microenvironment, which is closely related to immune cell function and edits tumor immunology [33].…”

Section: Discussionmentioning

confidence: 99%

Discovery and validation of immune- related long non-coding RNA biomarkers associated with prognosis in hepatocellular carcinoma

Liu

Song

Zhu

et al. 2020

Preprint

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Background : Hepatocellular carcinoma (HCC) is one of the most common clinical malignant tumors, resulting in high mortality and poor prognosis. Studies have found that LncRNA plays an important role in the onset, metastasis and recurrence of hepatocellular carcinoma. The immune system plays a vital role in the development, progression, metastasis and recurrence of cancer. Therefore, immune-related lncRNA can be used as a novel biomarker to predict the prognosis of hepatocellular carcinoma. Methods : The transcriptome data and clinical data of HCC patients were obtained by using The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA‑LIHC), and immune-related genes were extracted from the Molecular Signatures Database (IMMUNE RESPONSE M19817 and IMMUNE SYSTEM PROCESS M13664). By constructing the co-expression network and Cox regression analysis, 13 immune-lncRNAs was identified to predict the prognosis of HCC patients. Patients were divided into high risk group and low risk group by using the risk score formula, and the difference in overall survival (OS) between the two groups was reflected by Kaplan-Meier survival curve. The time - dependent receiver operating characteristics (ROC) analysis and principal component analysis (PCA) were used to evaluate 13 immune -lncRNAs signature. Results : Through TCGA - LIHC extracted from 343 cases of patients with hepatocellular carcinoma RNA - Seq data and clinical data, 331 immune-related genes were extracted from the Molecular Signatures Database , co-expression networks and Cox regression analysis were constructed, 13 immune-lncRNAs signature was identified as biomarkers to predict the prognosis of patients. At the same time using the risk score median divided the patients into high risk and low risk groups, and through the Kaplan-Meier survival curve analysis found that high-risk group of patients' overall survival (OS) less low risk group of patients. The AUC value of the ROC curve is 0.828, and principal component analysis (PCA) results showed that patients could be clearly divided into two parts by immune-lncRNAs, which provided evidence for the use of 13 immune-lncRNAs signature as prognostic markers. Conclusion : Our study identified 13 immune-lncRNAs signature that can effectively predict the prognosis of HCC patients, which may be a new prognostic indicator for predicting clinical outcomes.

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“…Apparently, ITH of the microenvironment is neatly illustrated by the density, distribution, and composition of TICs and is likely correlated with tumor differentiation[ 74 ], which reveals the coordination of the tumoral functional phenotype and immune infiltration. To deeply explore the interaction between TICs and ITH, various algorithms have been developed to quantify the composition of immune infiltration using sequencing data[ 75 - 78 ] and expand the effectiveness of immune function assessment enormously[ 62 , 79 ]. Coincidentally, the latest two studies integrated DNA-seq, RNA-seq, T-cell receptor (TCR)-seq, neoantigen analysis, and other methods to uncover the role of functional heterogeneity in immune evasion[ 64 , 79 ].…”

Section: Functional Heterogeneity Orchestrates the Tumor Ecosystemmentioning

confidence: 99%

“…To deeply explore the interaction between TICs and ITH, various algorithms have been developed to quantify the composition of immune infiltration using sequencing data[ 75 - 78 ] and expand the effectiveness of immune function assessment enormously[ 62 , 79 ]. Coincidentally, the latest two studies integrated DNA-seq, RNA-seq, T-cell receptor (TCR)-seq, neoantigen analysis, and other methods to uncover the role of functional heterogeneity in immune evasion[ 64 , 79 ]. Cancer cells across different regions present different immunogenicity and escape immune surveillance in distinct ways, such as a decrease in immune cell infiltration, loss of heterozygosity of human leukocyte antigen, low TCR clonality, and immunoediting[ 64 ].…”

Section: Functional Heterogeneity Orchestrates the Tumor Ecosystemmentioning

confidence: 99%

Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies

Zhang

Lou

Bai

2020

WJG

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Hepatocellular carcinoma (HCC) is characterized by high heterogeneity in both intratumoral and interpatient manners. While interpatient heterogeneity is related to personalized therapy, intratumoral heterogeneity (ITH) largely influences the efficacy of therapies in individuals. ITH contributes to tumor growth, metastasis, recurrence, and drug resistance and consequently limits the prognosis of patients with HCC. There is an urgent need to understand the causes, characteristics, and consequences of tumor heterogeneity in HCC for the purposes of guiding clinical practice and improving survival. Here, we summarize the studies and technologies that describe ITH in HCC to gain insight into the origin and evolutionary process of heterogeneity. In parallel, evidence is collected to delineate the dynamic relationship between ITH and the tumor ecosystem. We suggest that conducting comprehensive studies of ITH using single-cell approaches in temporal and spatial dimensions, combined with population-based clinical trials, will help to clarify the clinical implications of ITH, develop novel intervention strategies, and improve patient prognosis.

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Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma

Cited by 146 publications

References 43 publications

Expression of Cancer testis Antigens in Tumor-adjacent Normal Liver Predicts Post-resection Recurrence of Hepatocellular Carcinoma

Expression of Cancer testis Antigens in Tumor-adjacent Normal Liver Predicts Post-resection Recurrence of Hepatocellular Carcinoma

Discovery and validation of immune- related long non-coding RNA biomarkers associated with prognosis in hepatocellular carcinoma

Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies

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