GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

Beek, Adriaan A. van; Zhou, Guoying; Doukas, Michail; Boor, Patrick P.C.; Noordam, Lisanne; Mancham, Shanta; Carrascosa, Lucia Campos; Heide-Mulder, Marieke van der; Polak, Wojciech; IJzermans, Jan N.M.; Pan, Qiuwei; Heirman, Carlo; Mahne, Ashley E.; Bucktrout, Samantha; Bruno, Marco J.; Sprengers, Dave; Kwekkeboom, Jaap

doi:10.1002/ijc.32181

Cited by 47 publications

(30 citation statements)

References 46 publications

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“…We also found that five kinds of immune cells were significantly positively related to the signature, including activated mast cells, M0 macrophages, resting dendritic cells, and activated memory CD4 T cells. It has been reported that tumor infiltration by T and B cells can improve the survival rate of patients with HCC (24)(25)(26)(27). Macrophages in HCC are linked to a good prognosis of HCC, and low immune cell infiltration in hepatocellular carcinoma is associated with the presence of neutrophils, NK cells and resting mast cells (28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Profiling of Five Immune-Related lncRNAs for a Prognostic Model of Hepatocellular Carcinoma

Wei

Liu

et al. 2021

Front. Oncol.

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Hepatocellular carcinoma (HCC), one of the most common tumors worldwide, has the fifth highest mortality rate, which is increasing every year. At present, many studies have revealed that immunotherapy has an important effect on many malignant tumors. The main purpose of our research was to verify and establish a new immune-related lncRNA model and to explore the potential immune mechanisms. We analysed the pathways and mechanisms of immune-related lncRNAs by bioinformatics analysis, screened key lncRNAs based on Cox regression analysis, and determined the characteristics of the immune-related lncRNAs. On this basis, a predictive model was established. Through a comparison of specificity and sensitivity, we found that the constructed model was superior to the known markers of HCC. Then, the cell types were identified by the relative subgroup (CIBERSORT) algorithm for RNA transcripts. A signature model was eventually constructed, and we proved that it was a survival factor for HCC. Moreover, five kinds of immune cells were significantly positively correlated with the signature. The results indicated that these five kinds of lncRNAs may be related to the immune infiltration of hepatocellular carcinoma. To verify these findings, we selected the top coexpressed lncRNA, AC099850.3, for further study. We found that AC099850.3 could promote the migration and proliferation of hepatocellular carcinoma cells in vitro. RT-PCR experiments found that AC099850.3 could promote the expression of the cell cycle molecules BUB1, CDK1, PLK1, and TTK, and western blotting to prove that the expression of the molecules CD155 and PD-L1 was inhibited in the interference group. In conclusion, we used five kinds of immune-related lncRNAs to construct prognostic signatures to explore the mechanism, which provides a new way to study therapies for HCC.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Profiling of Five Immune-Related lncRNAs for a Prognostic Model of Hepatocellular Carcinoma

Wei

Liu

et al. 2021

Front. Oncol.

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“…For HCC, a proof-of-concept pre-clinical experiment demonstrated that agonistic targeting of GITR with a GITR ligand or activating GITR antibody amplified the ex-vivo activity of tumor-infiltrating T-cells in HCC. This was illustrated by CD8+ T cell proliferation and granzyme B expression [105]. Targeting GITR and PD1 may improve anti-cancer T-cell in some patients and GITR is a promising immunotherapy target in HCC.…”

Section: Role Liver Directed Therapies Associated With Immunotherapymentioning

confidence: 99%

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

Viveiros

Riaz

Lewandowski

et al. 2019

Cancers

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The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC.

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“…Recently, PD-1 blockade and activation of GITR could synergistically induce the activation of T cells [163]. In addition, agonistic targeting of GITR was shown to augment TIL functionality in hepatocellular carcinoma [164].…”

Section: Immunotherapeutic Approaches Against Cancermentioning

confidence: 99%

Current Perspectives in Cancer Immunotherapy

Christofi

Baritaki

Falzone

et al. 2019

Cancers

165

121

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Different immunotherapeutic approaches have proved to be of significant clinical value to many patients with different types of advanced cancer. However, we need more precise immunotherapies and predictive biomarkers to increase the successful response rates. The advent of next generation sequencing technologies and their applications in immuno-oncology has helped us tremendously towards this aim. We are now moving towards the realization of personalized medicine, thus, significantly increasing our expectations for a more successful management of the disease. Here, we discuss the current immunotherapeutic approaches against cancer, including immune checkpoint blockade with an emphasis on anti-PD-L1 and anti-CTLA-4 monoclonal antibodies. We also analyze a growing list of other co-inhibitory and co-stimulatory markers and emphasize the mechanism of action of the principal pathway for each of these, as well as on drugs that either have been FDA-approved or are under clinical investigation. We further discuss recent advances in other immunotherapies, including cytokine therapy, adoptive cell transfer therapy and therapeutic vaccines. We finally discuss the modulation of gut microbiota composition and response to immunotherapy, as well as how tumor-intrinsic factors and immunological processes influence the mutational and epigenetic landscape of progressing tumors and response to immunotherapy but also how immunotherapeutic intervention influences the landscape of cancer neoepitopes and tumor immunoediting.

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GITR ligation enhances functionality of tumor‐infiltrating T cells in hepatocellular carcinoma

Cited by 47 publications

References 46 publications

Bioinformatics Profiling of Five Immune-Related lncRNAs for a Prognostic Model of Hepatocellular Carcinoma

Bioinformatics Profiling of Five Immune-Related lncRNAs for a Prognostic Model of Hepatocellular Carcinoma

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

Current Perspectives in Cancer Immunotherapy

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