Immunotherapy Updates in Advanced Hepatocellular Carcinoma

Singh, Amisha; Beechinor, Ryan J.; Huynh, Jasmine C.; Li, Daneng; Dayyani, Farshid; Valerin, Jennifer Brooke; Hendifar, Andrew Eugene; Gong, Jun; Cho, May

doi:10.3390/cancers13092164

Cited by 18 publications

(13 citation statements)

References 83 publications

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“…PD-L1/PD-1 axis plays a crucial role in inducing apoptosis of cytotoxic T cells, thus maintaining an immunosuppressive microenvironment [64] that contributes to nurture tumor growth and progression. Hence, antibodies targeting PD-L1 or PD-1 have proved effective in some solid cancers [65,66]. In PCa there are not equivalent effects, which suggests that our understanding on PD-L1/PD-1 axis in this neoplasia is still limited.…”

Section: Discussionmentioning

confidence: 99%

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Antognelli

Mandarano

Prosperi

et al. 2021

Cancers

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Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.

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Section: Discussionmentioning

confidence: 99%

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Antognelli

Mandarano

Prosperi

et al. 2021

Cancers

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“…Immunotherapy to revive dysfunctional/exhausted anti-tumor immunity is a promising strategy for many different types of cancers including HCC ( Singh et al, 2021 ). U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved immunotherapeutic agents targeting the PD-L1, PD-L2/PD1 pathway in HCC patients ( Sangro et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

Chinnadurai

Porter

Patel

et al. 2021

Front. Cell Dev. Biol.

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B7 family proteins serve as checkpoint molecules that protect tumors from T cell mediated lysis. Tryptophan degrading enzymes indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3 dioxygenase (TDO) also induce T cell immune tolerance. However, little is known about the relative contribution of B7 molecules, tryptophan degrading enzymes, as well as the impact of tumor and stromal cell interactions to the development of immunosuppressive tumor microenvironment. To investigate such interactions, we used a tripartite model of human hepatocellular carcinoma cell line (HepG2) and mesenchymal stromal cells (MSCs) co-cultured with peripheral blood mononuclear cells (PBMCs). Co-culture of HepG2 cells and activated PBMCs demonstrate that HepG2 cells undergo PBMC mediated cytolysis, despite constitutive expression of B7-H3 and upregulation of PD-L1 by IFNγ. Knockdown of B7-H3, PD-L1 or IDO does not modulate PBMC mediated lysis of HepG2 cells. However, TNFα preactivation enhances lysis of HepG2 cells, and blocking of TNFα production from PBMCs protects HepG2 cells. On the other hand, MSCs protect HepG2 cells from PBMC mediated lysis, even in the presence of TNFα. Further investigation showed that MSC mediated protection is associated with the unique secretome profile of upregulated and downregulated cytokines and chemokines. IFNγ activated MSCs are superior to TNFα activated or control MSCs in protecting HepG2 cells. Blockade of IFNγ driven IDO activity completely abolishes the ability of MSCs to protect HepG2 cells from cytolysis by PBMCs. These results suggest that inhibition of IFNγ activation of IDO induction in stromal cells, combined with usage of TNFα, could be a novel immunotherapeutic strategy to induce regression of hepatocellular carcinoma.

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“…When compared to sorafenib, this new agent presents a similar safety profile [ 70 ]. In the latest guidelines, the combination of atezolizumab/bevacizumab or tremelimumab/durvalumab is considered the first line treatment for advanced HCC [ 71 ].…”

Section: Combined Treatmentsmentioning

confidence: 99%

Transarterial Chemoembolization for Hepatocellular Carcinoma: Why, When, How?

Kotsifa

Vergadis

Vailas

et al. 2022

JPM

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Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. It is principally associated with liver cirrhosis and chronic liver disease. The major risk factors for the development of HCC include viral infections (HBV, HCV), alcoholic liver disease (ALD,) and non-alcoholic fatty liver disease (NAFLD). The optimal treatment choice is dictated by multiple variables such as tumor burden, liver function, and patient’s health status. Surgical resection, transplantation, ablation, transarterial chemoembolization (TACE), and systemic therapy are potentially useful treatment strategies. TACE is considered the first-line treatment for patients with intermediate stage HCC. The purpose of this review was to assess the indications, the optimal treatment schedule, the technical factors associated with TACE, and the overall application of TACE as a personalized treatment for HCC.

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Immunotherapy Updates in Advanced Hepatocellular Carcinoma

Cited by 18 publications

References 83 publications

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

Hepatocellular Carcinoma Cells Are Protected From Immunolysis by Mesenchymal Stromal Cells Through Indoleamine 2,3 Dioxygenase

Transarterial Chemoembolization for Hepatocellular Carcinoma: Why, When, How?

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