Cancers

2024

Jump to: 2023, 2022

18 pages, 6226 KiB

Open AccessReview

by Nevin Varghese, Amry Majeed, Suraj Nyalakonda, Tina Boortalary, Dina Halegoua-DeMarzio and Hie-Won Hann

Cancers 2024, 16(4), 777; https://doi.org/10.3390/cancers16040777 - 14 Feb 2024

Viewed by 1296

Abstract

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the [...] Read more.

Chronic hepatitis B virus (HBV) infection is the largest global cause of hepatocellular carcinoma (HCC). Current HBV treatment options include pegylated interferon-alpha and nucleos(t)ide analogues (NAs), which have been shown to be effective in reducing HBV DNA levels to become undetectable. However, the literature has shown that some patients have persistent risk of developing HCC. The mechanism in which this occurs has not been fully elucidated. However, it has been discovered that HBV’s covalently closed circular DNA (cccDNA) integrates into the critical HCC driver genes in hepatocytes upon initial infection; additionally, these are not targets of current NA therapies. Some studies suggest that HBV undergoes compartmentalization in peripheral blood mononuclear cells that serve as a sanctuary for replication during antiviral therapy. The aim of this review is to expand on how patients with HBV may develop HCC despite years of HBV viral suppression and carry worse prognosis than treatment-naive HBV patients who develop HCC. Furthermore, HCC recurrence after initial surgical or locoregional treatment in this setting may cause carcinogenic cells to behave more aggressively during treatment. Curative novel therapies which target the life cycle of HBV, modulate host immune response, and inhibit HBV RNA translation are being investigated. Full article

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2023

Jump to: 2024, 2022

27 pages, 41679 KiB

Open AccessArticle

A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss of Ppp2r5d

by Judit Domènech Omella, Emanuela E. Cortesi, Iris Verbinnen, Michiel Remmerie, Hanghang Wu, Francisco J. Cubero, Tania Roskams and Veerle Janssens

Cancers 2023, 15(16), 4193; https://doi.org/10.3390/cancers15164193 - 21 Aug 2023

Viewed by 1428

Abstract

Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of Ppp2r5d, encoding the B56δ subunit of Protein Phosphatase 2A [...] Read more.

Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of Ppp2r5d, encoding the B56δ subunit of Protein Phosphatase 2A (PP2A), results in spontaneous HCC development in mice via a c-MYC-dependent mechanism. In the present study, we aimed to examine the role of Ppp2r5d in an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Ppp2r5d deletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggesting Ppp2r5d may be haploinsufficient. Ppp2r5d-deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues of Ppp2r5d-deficient mice. We also found increased YAP activation in Ppp2r5d-deficient tumors. Remarkably, in older mice, Ppp2r5d deletion resulted in cHCC-CCA development in this model, with the CCA component showing increased expression of progenitor markers (SOX9 and EpCAM). Finally, we observed an upregulation of Ppp2r5d in tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism of Ppp2r5d expression, and suggestive of the involvement of Ppp2r5d in a negative feedback regulation restricting tumor growth. Our study highlights the tumor-suppressive role of mouse PP2A-B56δ in both HCC and cHCC-CCA, which may have important implications for human PLC development and targeted treatment. Full article

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17 pages, 2288 KiB

Open AccessReview

New Era of Immune-Based Therapy in Intrahepatic Cholangiocarcinoma

by Etsushi Kawamura, Tsutomu Matsubara and Norifumi Kawada

Cancers 2023, 15(15), 3993; https://doi.org/10.3390/cancers15153993 - 06 Aug 2023

Cited by 2 | Viewed by 1934

Abstract

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10–15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. [...] Read more.

Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10–15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC. Full article

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24 pages, 1548 KiB

Open AccessReview

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

by Jing Fang, Séverine Celton-Morizur and Chantal Desdouets

Cancers 2023, 15(14), 3723; https://doi.org/10.3390/cancers15143723 - 22 Jul 2023

Cited by 4 | Viewed by 2144

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty [...] Read more.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC. Full article

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14 pages, 4238 KiB

Open AccessArticle

Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma

by Naoshi Nishida, Tomoko Aoki, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima and Masatoshi Kudo

Cancers 2023, 15(8), 2379; https://doi.org/10.3390/cancers15082379 - 20 Apr 2023

Cited by 4 | Viewed by 1292

Abstract

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status [...] Read more.

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a “non-inflamed” tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (p = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the “inflamed” group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (p = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the “non-inflamed” tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA. Full article

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13 pages, 2982 KiB

Open AccessArticle

Deep Learning Model Based on Contrast-Enhanced Computed Tomography Imaging to Predict Postoperative Early Recurrence after the Curative Resection of a Solitary Hepatocellular Carcinoma

by Masahiko Kinoshita, Daiju Ueda, Toshimasa Matsumoto, Hiroji Shinkawa, Akira Yamamoto, Masatsugu Shiba, Takuma Okada, Naoki Tani, Shogo Tanaka, Kenjiro Kimura, Go Ohira, Kohei Nishio, Jun Tauchi, Shoji Kubo and Takeaki Ishizawa

Cancers 2023, 15(7), 2140; https://doi.org/10.3390/cancers15072140 - 04 Apr 2023

Cited by 5 | Viewed by 1534

Abstract

We aimed to develop the deep learning (DL) predictive model for postoperative early recurrence (within 2 years) of hepatocellular carcinoma (HCC) based on contrast-enhanced computed tomography (CECT) imaging. This study included 543 patients who underwent initial hepatectomy for HCC and were randomly classified [...] Read more.

We aimed to develop the deep learning (DL) predictive model for postoperative early recurrence (within 2 years) of hepatocellular carcinoma (HCC) based on contrast-enhanced computed tomography (CECT) imaging. This study included 543 patients who underwent initial hepatectomy for HCC and were randomly classified into training, validation, and test datasets at a ratio of 8:1:1. Several clinical variables and arterial CECT images were used to create predictive models for early recurrence. Artificial intelligence models were implemented using convolutional neural networks and multilayer perceptron as a classifier. Furthermore, the Youden index was used to discriminate between high- and low-risk groups. The importance values of each explanatory variable for early recurrence were calculated using permutation importance. The DL predictive model for postoperative early recurrence was developed with the area under the curve values of 0.71 (test datasets) and 0.73 (validation datasets). Postoperative early recurrence incidences in the high- and low-risk groups were 73% and 30%, respectively (p = 0.0057). Permutation importance demonstrated that among the explanatory variables, the variable with the highest importance value was CECT imaging analysis. We developed a DL model to predict postoperative early HCC recurrence. DL-based analysis is effective for determining the treatment strategies in patients with HCC. Full article

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23 pages, 532 KiB

Open AccessReview

Systemic Therapy for Advanced Hepatocellular Carcinoma: Current Stand and Perspectives

by Daniel M. Girardi, Lara P. Sousa, Thiago A. Miranda, Fernanda N. C. Haum, Gabriel C. B. Pereira and Allan A. L. Pereira

Cancers 2023, 15(6), 1680; https://doi.org/10.3390/cancers15061680 - 09 Mar 2023

Cited by 7 | Viewed by 2769

Abstract

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because [...] Read more.

Hepatocellular carcinoma often develops in the context of chronic liver disease. It is the sixth most frequently diagnosed cancer and the third most common cause of cancer-related mortality worldwide. Although the mainstay of therapy is surgical resection, most patients are not eligible because of liver dysfunction or tumor extent. Sorafenib was the first tyrosine kinase inhibitor that improved the overall survival of patients who failed to respond to local therapies or had advanced disease, and for many years, it was the only treatment approved for the first-line setting. However, in recent years, trials have demonstrated an improvement in survival with treatments based on immunotherapy and new targeting agents, thereby extending the treatment options. A phase III trial showed that a combination of immunotherapy and targeted therapy, including atezolizumab plus bevacizumab, improved survival in the first-line setting, and is now considered the new standard of care. Other agents and combinations are being tested, including the combination of nivolumab plus ipilimumab and tremelimumab plus durvalumab, and they reportedly have clinical benefits. The aim of this manuscript is to review the latest approved therapeutic options in first- and second-line settings for advanced HCC and discuss future perspectives. Full article

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13 pages, 3797 KiB

Open AccessArticle

Relationship between Being Overweight and Clinical Outcomes of Ablation Therapy for Hepatocellular Carcinoma under Ultrasound Guidance: A Retrospective Analysis

by Takeshi Hatanaka, Yutaka Yata, Naoto Saito, Sachi Nakano, Yuya Nakano, Yoichi Hazama, Sachiko Yoshida, Yoko Hachisu, Yoshiki Tanaka, Teruo Yoshinaga, Atsushi Naganuma and Satoru Kakizaki

Cancers 2023, 15(4), 1289; https://doi.org/10.3390/cancers15041289 - 17 Feb 2023

Viewed by 1347

Abstract

This study aimed to investigate the effect of being overweight on the outcome of ablation therapy for patients with early-stage hepatocellular carcinoma (HCC). This retrospective study included 198 patients with HCC who underwent radiofrequency ablation or microwave ablation at Gunma Saiseikai Maebashi Hospital [...] Read more.

This study aimed to investigate the effect of being overweight on the outcome of ablation therapy for patients with early-stage hepatocellular carcinoma (HCC). This retrospective study included 198 patients with HCC who underwent radiofrequency ablation or microwave ablation at Gunma Saiseikai Maebashi Hospital between April 2017 and December 2021. We divided the patients into two groups based on their body mass index (BMI): overweight (BMI ≥ 25 kg/m², n = 74 (37.4%)) and non-overweight (BMI < 25 kg/m², n = 124 (62.6%)). The technical success rates (TSRs) in the first session were 78.4% and 90.3% in overweight and non-overweight patients, respectively, with a significant difference (p = 0.03). Additional ablation therapy for residual tumors was required in 15 (20.3%) overweight and 11 (8.9%) non-overweight patients (p = 0.03), resulting in 95.9% and 99.2% TSRs at the final session, respectively, without a significant difference (p = 0.3). While local tumor progression and distant recurrence rates were not significantly different between the two groups, overall survival was better in overweight patients than in non-overweight patients (p < 0.001). Despite the potential adverse impact of being overweight on public health problems, the present findings showed the relationship between being overweight and improved survival. The negative aspects of being overweight might remain as minor technical issues in HCC patients receiving ablation therapy. Full article

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11 pages, 1621 KiB

Open AccessArticle

Comparable Overall Survival in Patients with Hepatocellular Carcinoma Diagnosed within and outside a Surveillance Programme: The Potential Impact of Liver Cirrhosis

by Rosemary E. Faulkes, Zaira Rehman, Swetha Palanichamy, Nekisa Zakeri, Chris Coldham, Bobby V. M. Dasari, M. Thamara P. R. Perera, Neil Rajoriya, Shishir Shetty and Tahir Shah

Cancers 2023, 15(3), 978; https://doi.org/10.3390/cancers15030978 - 03 Feb 2023

Cited by 1 | Viewed by 1704

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing [...] Read more.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death, and its incidence is rising. Mortality from HCC is predicted to increase by 140% by 2035. Surveillance of high-risk patients with cirrhosis or chronic liver disease may be one means of reducing HCC mortality, but the level of supporting evidence for international guidelines is low/moderate. This study explores the real-world experience of HCC surveillance at a tertiary referral centre. Electronic patient records for all new HCCs diagnosed between August 2012 and December 2021 were retrospectively reviewed. Patient and tumour characteristics were evaluated, including the co-existence of chronic liver disease, cancer treatment and survival, and categorised according to HCC diagnosis within or outside a surveillance programme. Patients with HCC who presented through surveillance had smaller tumours diagnosed at an earlier stage, but this did not translate into improved overall survival. All patients in surveillance had chronic liver disease, including 91% (n = 101) with cirrhosis, compared to 45% (n = 29) in the non-surveillance cohort. We propose that the immune dysfunction associated with cirrhosis predisposes patients to a more aggressive tumour biology than the largely non-cirrhotic population in the non-surveillance group. Full article

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12 pages, 1147 KiB

Open AccessArticle

Effectiveness of Repeated Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma—Consideration of the Locations of Target Lesions

by Shigeki Yano, Tomoki Kimura, Tomokazu Kawaoka, Takahiro Kinami, Shintaro Yamasaki, Yusuke Johira, Masanari Kosaka, Kei Amioka, Kensuke Naruto, Yuwa Ando, Kenji Yamaoka, Yasutoshi Fujii, Shinsuke Uchikawa, Hatsue Fujino, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Wataru Okamoto, Masami Yamauchi, Michio Imamura, Junichi Hirokawa, Yasushi Nagata, Hiroshi Aikata and Shiro Oka Show full author list Hide full author list

Cancers 2023, 15(3), 846; https://doi.org/10.3390/cancers15030846 - 30 Jan 2023

Viewed by 1621

Abstract

The present study retrospectively evaluated the efficacy of stereotactic body radiation therapy (SBRT), including repeated SBRT, for hepatocellular carcinoma. Participants comprised 220 HCC patients treated with SBRT in Hiroshima University Hospital between December 2008 and December 2021. Median overall survival (OS) and disease-free [...] Read more.

The present study retrospectively evaluated the efficacy of stereotactic body radiation therapy (SBRT), including repeated SBRT, for hepatocellular carcinoma. Participants comprised 220 HCC patients treated with SBRT in Hiroshima University Hospital between December 2008 and December 2021. Median overall survival (OS) and disease-free survival were 52 months (range, 45–64 months) and 17 months (range, 14–23 months), respectively. The 5-year local tumor recurrence rate was 3.4% (95% confidence interval (CI), 1.3–6.9%). Fifty-three patients underwent repeated SBRT (twice, 53 cases; three times, 10 cases; four times, 4 cases; five times, 1 case). Median interval between first and second SBRT was 20 months. Median OS from first SBRT was 76 months (95% CI, 50–102 months). Among patients with repeated SBRT, only one case showed local recurrence after second SBRT. Albumin–bilirubin score increased significantly from 6 to 12 months after repeated SBRT, both in the same segment and in remote segments, but the increase was not significant in the same segment. Only one case of grade 3 bile duct stricture was observed in patients who were treated with repeated SBRT. In conclusion, repeated SBRT provides good local control and a low risk of side effects. Full article

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13 pages, 2476 KiB

Open AccessArticle

Thrombospondin-2 as a Predictive Biomarker for Hepatocellular Carcinoma after Hepatitis C Virus Elimination by Direct-Acting Antiviral

by Takayuki Matsumae, Takahiro Kodama, Yuki Tahata, Yuta Myojin, Akira Doi, Akira Nishio, Ryoko Yamada, Yasutoshi Nozaki, Masahide Oshita, Naoki Hiramatsu, Naoki Morishita, Kazuyoshi Ohkawa, Taizo Hijioka, Mitsuru Sakakibara, Yoshinori Doi, Naruyasu Kakita, Takayuki Yakushijin, Ryotaro Sakamori, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara Show full author list Hide full author list

Cancers 2023, 15(2), 463; https://doi.org/10.3390/cancers15020463 - 11 Jan 2023

Cited by 2 | Viewed by 2305

Abstract

We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis C virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total of 786 CHC patients without an HCC history who [...] Read more.

We evaluated the value of secreted glycoprotein thrombospondin-2 (TSP-2) to predict hepatocellular carcinoma (HCC) occurrence in chronic hepatitis C (CHC) patients after Hepatitis C virus (HCV) elimination by direct-acting antiviral agents (DAAs). A total of 786 CHC patients without an HCC history who achieved a sustained virological response (SVR) with DAAs were randomly assigned 2:1, with 524 patients as the derivation cohort and 262 patients as the validation cohort. Serum TSP-2 levels at the end of treatment were measured by enzyme-linked immunosorbent assay (ELISA). In the derivation cohort, the cumulative HCC rate was significantly higher in the high TSP-2 group than in the low TSP-2 group. Multivariate Cox proportional hazards analysis revealed that TSP-2, α-fetoprotein (AFP), and the fibrosis-4 (FIB-4) index were independent HCC risk factors. The area under the receiver operating characteristic curve (AUROC) of the score calculated from these three factors (AFT score) for predicting HCC was 0.83, which was significantly higher than that of each factor alone (TSP-2: 0.70, AFP: 0.72, FIB-4: 0.69). The AFT score was used to stratify patients according to the risk of HCC occurrence in the validation cohort. Lastly, in patients with a FIB-4 index < 3.25, the serum TSP-2 levels could be used to identify those patients with a high risk of HCC occurrence. Serum TSP-2 levels are a predictive biomarker of HCC occurrence in CHC patients after HCV elimination by DAA treatment. The AFT score using TSP-2, AFP, and the FIB-4 index may identify those who require HCC surveillance. Full article

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22 pages, 4177 KiB

Open AccessArticle

PVRIG Expression Is an Independent Prognostic Factor and a New Potential Target for Immunotherapy in Hepatocellular Carcinoma

by David Jeremie Birnbaum, Maelle Picard, Quentin Da Costa, Thomas Delayre, Pascal Finetti, Olivier Cabaud, Emilie Agavnian, Bernadette De Rauglaudre, Emilie Denicolaï, François Bertucci and Emilie Mamessier

Cancers 2023, 15(2), 447; https://doi.org/10.3390/cancers15020447 - 10 Jan 2023

Cited by 2 | Viewed by 2683

Abstract

Hepatocellular carcinoma (HCC) is a frequent and deadly cancer in need of new treatments. Immunotherapy has shown promising results in several solid tumors. The TIGIT/DNAM-1 axis gathers targets for new immune checkpoint inhibitors (ICIs). Here, we aimed at highlighting the potential of this [...] Read more.

Hepatocellular carcinoma (HCC) is a frequent and deadly cancer in need of new treatments. Immunotherapy has shown promising results in several solid tumors. The TIGIT/DNAM-1 axis gathers targets for new immune checkpoint inhibitors (ICIs). Here, we aimed at highlighting the potential of this axis as a new therapeutic option for HCC. For this, we built a large transcriptomic database of 683 HCC samples, clinically annotated, and 319 normal liver tissues. We interrogated this database for the transcriptomic expression of each member of the TIGIT/DNAM-1 axis and tested their prognostic value for survival. We then focused on the most discriminant one for these criteria, i.e., PVRIG, and analyzed the clinical characteristics, the disease-free and overall survivals, and biological pathways associated with PVRIG High tumors. Among all members of the TIGIT/DNAM-1 axis, PVRIG expression was higher in tumors than in normal liver, was heterogeneous across tumors, and was the only member with independent prognostic value for better survival. PVRIG High tumors were characterized by a higher lymphocytic infiltrate and enriched for signatures associated with tertiary lymphoid structures and better anti-tumor immune response. These results suggest that patients with PVRIG High tumors might be good candidates for immune therapy involving ICIs, notably ICIs targeting the TIGIT/DNAM-1 axis. Further functional and clinical validation is urgently required. Full article

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2022

Jump to: 2024, 2023

34 pages, 1068 KiB

Open AccessReview

The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network

by Camilla Volponi, Aurora Gazzillo and Eduardo Bonavita

Cancers 2022, 14(24), 6151; https://doi.org/10.3390/cancers14246151 - 13 Dec 2022

Cited by 4 | Viewed by 3212

Abstract

HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier [...] Read more.

HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB. Full article

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14 pages, 1220 KiB

Open AccessArticle

Circulating Cell-Free DNA Profiling Predicts the Therapeutic Outcome in Advanced Hepatocellular Carcinoma Patients Treated with Combination Immunotherapy

by Takayuki Matsumae, Takahiro Kodama, Yuta Myojin, Kazuki Maesaka, Ryotaro Sakamori, Ayako Takuwa, Keiko Oku, Daisuke Motooka, Yoshiyuki Sawai, Masahide Oshita, Tasuku Nakabori, Kazuyoshi Ohkawa, Masanori Miyazaki, Satoshi Tanaka, Eiji Mita, Seiichi Tawara, Takayuki Yakushijin, Yasutoshi Nozaki, Hideki Hagiwara, Yuki Tahata, Ryoko Yamada, Hayato Hikita, Tomohide Tatsumi and Tetsuo Takehara Show full author list Hide full author list

Cancers 2022, 14(14), 3367; https://doi.org/10.3390/cancers14143367 - 11 Jul 2022

Cited by 24 | Viewed by 3199

Abstract

Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that [...] Read more.

Combination immunotherapy with anti-programmed cell death1-ligand1 (PD-L1) and anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for patients with unresectable HCC (u-HCC). However, limited patients obtain clinical benefits. Cell-free DNA (cfDNA) in peripheral blood contains circulating tumor DNA (ctDNA) that reflects molecular abnormalities in tumor tissue. We investigated the potential of cfDNA/ctDNA as biomarkers for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. We enrolled a multicenter cohort of 85 HCC patients treated with atezolizumab and bevacizumab (Atezo/Bev) between 2020 and 2021. Pretreatment plasma was collected, and cfDNA levels were quantified. Ultradeep sequencing of cfDNA was performed with a custom-made panel for detecting mutations in 25 HCC-related cancer genes. We evaluated the association of cfDNA/ctDNA profiles and clinical outcomes. Patients with high plasma cfDNA levels showed a significantly lower response rate and shorter progression-free survival and overall survival (OS) than those with low cfDNA levels. ctDNA detected in 55% of HCC patients included the telomerase reverse transcriptase (TERT) promoter in 31% of these patients, tumor protein 53 (TP53) in 21%, catenin beta 1 (CTNNB1) in 13% and phosphatase and tensin homolog (PTEN) in 7%. The presence or absence of ctDNA did not predict the efficacy of Atezo/Bev therapy. Twenty-six patients with a TERT mutation had significantly shorter OS than those without. The presence of a TERT mutation and alpha-fetoprotein (AFP) ≥ 400 ng/mL were independent predictors of poor OS according to multivariate Cox proportional hazard analysis and could be used to stratify patients treated with Atezo/Bev therapy based on prognosis. In conclusion, pretreatment cfDNA/ctDNA profiling may be useful for predicting the therapeutic outcome in u-HCC patients treated with anti-PD-L1/VEGF therapy. Full article

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