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Cancers
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Tumor Microenvironment in Primary Liver Cancer
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Tumor Microenvironment in Primary Liver Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: 28 June 2024 | Viewed by 10337

Special Issue Editors

Dr. Stefania Mantovani

E-Mail Website
Guest Editor
Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS Policlinico, San Matteo, 27100 Pavia, Italy
Interests: hepatocellular carcinoma; cholangiocarcinoma; NK cells; tumor immunology; innate immunity; immunogenetics
Dr. Barbara Oliviero

E-Mail Website
Guest Editor
Division of Clinical Immunology and Infectious Diseases, Fondazione IRCCS San Matteo, 27100 Pavia, Italy
Interests: NK cells; liver cancer; tumor immunology; B cells; antibodies

Special Issue Information

Dear Colleagues,

We are honored to be the guest editors of this special issue of Cancers entitled "Tumor Microenvironment in Primary Liver Cancer" that will try to deeply understand the pivotal role of all players of the tumor microenvironment (TME) involved in the complex interplay with cancer cells.

Liver cancers, including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), remain a global health challenge and their incidence is growing worldwide. It is estimated that, by 2025, >1 million individuals will be affected by liver cancer annually.

The rapid development of multi-omics, single-cell technology and spatial tissue analysis have helped researchers to elucidate the complexity of TME and at the same time to classify the strong heterogeneity of liver cancer into major types.

In HCC, TME consists of a mixture of three major players including normal, fibrotic and neoplastic areas accompanied by distinct distribution patterns of tumorous, stromal and immune cells, which are relevant to the clinical outcome of patients. In-depth analysis of the immune TME disclosed distinct subclasses of patients showing differences in clinical prognosis and response to personalized treatment.

A desmoplastic stroma with a dense extracellular matrix, mainly enriched by cancer-associated fibroblasts, is the prominent feature of iCCA-TME that plays an important role for the biology and aggressiveness of iCCA. Immune subtypes in the iCCA-TME, with different populations and gene expression profiles as well as exhibiting different inflammatory and immune checkpoint pathways, limit the effect of targeted therapy and immunotherapy in a sizeable proportion of patients, further limiting the already limited therapeutic opportunities.

For this Special Issue of Cancers, we invite authors to submit contributions that will provide new insights into compositions and functions of the diverse cell types and their metabolomes, secretomes, exosomes, and other soluble factors, responsible for cancer heterogeneity and tumor evolution, in particular findings that could have a promising translational application.

Dr. Stefania Mantovani
Dr. Barbara Oliviero
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • liver cancer, hepatocellular carcinoma
  • cholangiocarcinoma
  • tumor immunology
  • immune system
  • tumor microenvironment
  • NK cells
  • cancer-associated fibroblast
  • extracellular vesicles
  • secretome

Published Papers (5 papers)

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Research

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24 pages, 4016 KiB  
Article
Multi-View Radiomics Feature Fusion Reveals Distinct Immuno-Oncological Characteristics and Clinical Prognoses in Hepatocellular Carcinoma
by Yu Gu, Hao Huang, Qi Tong, Meng Cao, Wenlong Ming, Rongxin Zhang, Wenyong Zhu, Yuqi Wang and Xiao Sun
Cancers 2023, 15(8), 2338; https://doi.org/10.3390/cancers15082338 - 17 Apr 2023
Cited by 4 | Viewed by 1793
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, and the pronounced intra- and inter-tumor heterogeneity restricts clinical benefits. Dissecting molecular heterogeneity in HCC is commonly explored by endoscopic biopsy or surgical forceps, but invasive tissue sampling and possible complications limit [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, and the pronounced intra- and inter-tumor heterogeneity restricts clinical benefits. Dissecting molecular heterogeneity in HCC is commonly explored by endoscopic biopsy or surgical forceps, but invasive tissue sampling and possible complications limit the broadeer adoption. The radiomics framework is a promising non-invasive strategy for tumor heterogeneity decoding, and the linkage between radiomics and immuno-oncological characteristics is worth further in-depth study. In this study, we extracted multi-view imaging features from contrast-enhanced CT (CE-CT) scans of HCC patients, followed by developing a fused imaging feature subtyping (FIFS) model to identify two distinct radiomics subtypes. We observed two subtypes of patients with distinct texture-dominated radiomics profiles and prognostic outcomes, and the radiomics subtype identified by FIFS model was an independent prognostic factor. The heterogeneity was mainly attributed to inflammatory pathway activity and the tumor immune microenvironment. The predominant radiogenomics association was identified between texture-related features and immune-related pathways by integrating network analysis, and was validated in two independent cohorts. Collectively, this work described the close connections between multi-view radiomics features and immuno-oncological characteristics in HCC, and our integrative radiogenomics analysis strategy may provide clues to non-invasive inflammation-based risk stratification. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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10 pages, 1744 KiB  
Article
Radiomic Analysis Based on Magnetic Resonance Imaging for Predicting PD-L2 Expression in Hepatocellular Carcinoma
by Yun-Yun Tao, Yue Shi, Xue-Qin Gong, Li Li, Zu-Mao Li, Lin Yang and Xiao-Ming Zhang
Cancers 2023, 15(2), 365; https://doi.org/10.3390/cancers15020365 - 05 Jan 2023
Cited by 10 | Viewed by 1694
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumour and the third leading cause of cancer death in the world. The emerging field of radiomics involves extracting many clinical image features that cannot be recognized by the human eye to provide information [...] Read more.
Hepatocellular carcinoma (HCC) is the sixth most common malignant tumour and the third leading cause of cancer death in the world. The emerging field of radiomics involves extracting many clinical image features that cannot be recognized by the human eye to provide information for precise treatment decision making. Radiomics has shown its importance in HCC identification, histological grading, microvascular invasion (MVI) status, treatment response, and prognosis, but there is no report on the preoperative prediction of programmed death ligand-2 (PD-L2) expression in HCC. The purpose of this study was to investigate the value of MRI radiomic features for the non-invasive prediction of immunotherapy target PD-L2 expression in hepatocellular carcinoma (HCC). A total of 108 patients with HCC confirmed by pathology were retrospectively analysed. Immunohistochemical analysis was used to evaluate the expression level of PD-L2. 3D-Slicer software was used to manually delineate volumes of interest (VOIs) and extract radiomic features on preoperative T2-weighted, arterial-phase, and portal venous-phase MR images. Least absolute shrinkage and selection operator (LASSO) was performed to find the best radiomic features. Multivariable logistic regression models were constructed and validated using fivefold cross-validation. The area under the receiver characteristic curve (AUC) was used to evaluate the predictive performance of each model. The results show that among the 108 cases of HCC, 50 cases had high PD-L2 expression, and 58 cases had low PD-L2 expression. Radiomic features correlated with PD-L2 expression. The T2-weighted, arterial-phase, and portal venous-phase and combined MRI radiomics models showed AUCs of 0.789 (95% CI: 0.702–0.875), 0.727 (95% CI: 0.632–0.823), 0.770 (95% CI: 0.682–0.875), and 0.871 (95% CI: 0.803–0.939), respectively. The combined model showed the best performance. The results of this study suggest that prediction based on the radiomic characteristics of MRI could noninvasively predict the expression of PD-L2 in HCC before surgery and provide a reference for the selection of immune checkpoint blockade therapy. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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18 pages, 3861 KiB  
Article
Comprehensive Analysis of Cuproptosis-Related Genes in Prognosis and Immune Infiltration of Hepatocellular Carcinoma Based on Bulk and Single-Cell RNA Sequencing Data
by Chenglei Yang, Yanlin Guo, Zongze Wu, Juntao Huang and Bangde Xiang
Cancers 2022, 14(22), 5713; https://doi.org/10.3390/cancers14225713 - 21 Nov 2022
Cited by 5 | Viewed by 2365
Abstract
Background: Studies on prognostic potential and tumor immune microenvironment (TIME) characteristics of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are limited. Methods: A multigene signature model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The cuproptosis-related multivariate [...] Read more.
Background: Studies on prognostic potential and tumor immune microenvironment (TIME) characteristics of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) are limited. Methods: A multigene signature model was constructed using the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The cuproptosis-related multivariate cox regression analysis and bulk RNA-seq-based immune infiltration analysis were performed. The results were verified using two cohorts. The enrichment of CRGs in T cells based on single-cell RNA sequencing (scRNA-seq) was performed. Real-time polymerase chain reaction (RT-PCR) and multiplex immunofluorescence staining were performed to verify the reliability of the conclusions. Results: A four-gene risk scoring model was constructed. Kaplan–Meier curve analysis showed that the high-risk group had a worse prognosis (p < 0.001). The time-dependent receiver operating characteristic (ROC) curve showed that the OS risk score prediction performance was good. These results were further confirmed in the validation queue. Meanwhile, the Tregs and macrophages were enriched in the cuproptosis-related TIME of HCC. Conclusions: The CRGs-based signature model could predict the prognosis of HCC. Treg and macrophages were significantly enriched in cuproptosis-related HCC, which was associated with the depletion of proliferating T cells. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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10 pages, 1299 KiB  
Article
The Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Poor Prognosis Factor in Patients with Hepatocellular Carcinoma: An Analysis of Microvessel Density
by Chun-Wei Huang, Sey-En Lin, Song-Fong Huang, Ming-Chin Yu, Jui-Hsiang Tang, Chi-Neu Tsai and Heng-Yuan Hsu
Cancers 2022, 14(21), 5428; https://doi.org/10.3390/cancers14215428 - 03 Nov 2022
Cited by 3 | Viewed by 1457
Abstract
The outcomes of patients with hepatocellular carcinoma (HCC) are unsatisfactory because of its high recurrence rate. The Vessels that encapsulate tumor clusters (VETC) pattern is a unique vascular structure. In this study, we investigated the clinical–pathological features of HCC patients with the VETC [...] Read more.
The outcomes of patients with hepatocellular carcinoma (HCC) are unsatisfactory because of its high recurrence rate. The Vessels that encapsulate tumor clusters (VETC) pattern is a unique vascular structure. In this study, we investigated the clinical–pathological features of HCC patients with the VETC pattern. We retrospectively reviewed patients with HCC who underwent curative hepatectomy at Chang Gung Memorial Hospital between 2007 and 2013. The form of the VETC pattern was established using an anti-CD31 stain. The results were classified into positive (VETC+) and negative (VETC−) patterns. We investigated and compared demographic data between these two groups. Overall, 174 patients were classified into either the VETC+ or VETC− groups. The median followed-up period was 80.5 months. There were significant differences in the number of hepatitis B carriers, the occurrence of vascular invasion, tumor size, TNM staging, microvessel density, and recurrence (all p < 0.05). Regarding the prediction of disease-free survival, after COX regression multivariate analysis, VETC+ remained independently associated with recurrent episodes (p = 0.003). The intra-tumoral microvessel density, demonstrated by CD-31, was the only clinical–pathological feature independently associated with VETC+. Our study demonstrated that the VETC pattern is an independent factor of poor prognosis for DFS. Higher intra-tumoral microvessel density was significantly associated with the VETC pattern. Further studies are needed to validate our findings. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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Review

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22 pages, 1927 KiB  
Review
Tumor-Infiltrating B Lymphocytes: Promising Immunotherapeutic Targets for Primary Liver Cancer Treatment
by Giulia Milardi and Ana Lleo
Cancers 2023, 15(7), 2182; https://doi.org/10.3390/cancers15072182 - 06 Apr 2023
Cited by 3 | Viewed by 2285
Abstract
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where [...] Read more.
Hepatocellular carcinoma and cholangiocarcinoma are the fourth most lethal primary cancers worldwide. Therefore, there is an urgent need for therapeutic strategies, including immune cell targeting therapies. The heterogeneity of liver cancer is partially explained by the characteristics of the tumor microenvironment (TME), where adaptive and innate immune system cells are the main components. Pioneering studies of primary liver cancers revealed that tumor-infiltrating immune cells and their dynamic interaction with cancer cells significantly impacted carcinogenesis, playing an important role in cancer immune evasion and responses to immunotherapy treatment. In particular, B cells may play a prominent role and have a controversial function in the TME. In this work, we highlight the effect of B lymphocytes as tumor infiltrates in relation to primary liver cancers and their potential prognostic value. We also present the key pathways underlying B-cell interactions within the TME, as well as the way that a comprehensive characterization of B-cell biology can be exploited to develop novel immune-based therapeutic approaches. Full article
(This article belongs to the Special Issue Tumor Microenvironment in Primary Liver Cancer)
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