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 132 publications

(84 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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“…On the other hand, Feun et al indicated that baseline plasma TGF-β level could be a predictive biomarker for the response to pembrolizumab [80], and clinical trials of combined blockade of PD-1/PD-L1 and TGF-β axis are ongoing (Table 3). Dong et al analyzed multiple tumors of the same patients for genetic structure, neoantigens, T cell receptor repertoires, and immune infiltrates, and found that only a few tumors were under the control of immunosurveillance and the majority carry a variety of immune escape mechanisms, even in a single case [81]. From this point of view, precise analysis of immune phenotype of HCC should contribute to the establishment of personalized immunotherapy in HCC cases.…”

Section: Current Limitation Of Immune Checkpoint Inhibitors and Challmentioning

confidence: 99%

Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma

Nishida

Kudo

2020

Cancers

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Immunotherapies are promising approaches for treating hepatocellular carcinomas (HCCs) refractory to conventional therapies. However, a recent clinical trial of immune checkpoint inhibitors (ICIs) revealed that anti-tumor responses to ICIs are not satisfactory in HCC cases. Therefore, it is critical to identify molecular markers to predict outcome and develop novel combination therapies that enhance the efficacy of ICIs. Recently, several attempts have been made to classify HCC based on genome, epigenome, and transcriptome analyses. These molecular classifications are characterized by unique clinical and histological features of HCC, as well immune phenotype. For example, HCCs exhibiting gene expression patterns with proliferation signals and stem cell markers are associated with the enrichment of immune infiltrates in tumors, suggesting immune-proficient characteristics for this type of HCC. However, the presence of activating mutations in β-catenin represents a lack of immune infiltrates and refractoriness to ICIs. Although the precise mechanism that links the immunological phenotype with molecular features remains controversial, it is conceivable that alterations of oncogenic cellular signaling in cancer may lead to the expression of immune-regulatory molecules and result in the acquisition of specific immunological microenvironments for each case of HCC. Therefore, these molecular and immune characteristics should be considered for the management of HCC using immunotherapy.

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Heterogeneous immunogenomic features and distinct escape mechanisms in multifocal hepatocellular carcinoma

Cited by 132 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

Immune Phenotype and Immune Checkpoint Inhibitors for the Treatment of Human Hepatocellular Carcinoma

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