Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma

Yu, Su Jong; Ma, Chi; Heinrich, Bernd; Brown, Zachary J.; Sandhu, Milan; Zhang, Qianfei; Fu, Qiong; Agdashian, David; Rosato, Umberto; Korangy, Firouzeh; Greten, Tim F.

doi:10.1016/j.jhep.2018.10.040

Cited by 115 publications

(95 citation statements)

References 45 publications

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“…37 In addition, we have demonstrated that adoptive cell transfer of CIK cells into tumor bearing mice induced inflammatory mediators (e.g., CX3CL1, IL-13) in the TME and an increase of tumor infiltrating MDSCs leading to impaired anti-tumor activity in two different murine HCC tumor models. 38 MDSCs efficiently suppressed the cytotoxic activity of CIK cells in vitro. Tadalafil treatment, a phosphodiesterase-5 (PDE5) inhibitor, has previously been shown to reverse MDSC suppressor function via ARG1 and iNOS blockade.…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 92%

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Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

Yu¹,

Greten²

2020

J Liver Cancer

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Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.

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Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 92%

“…Treatment of MDSCs with a PDE5 inhibitor suppressed MDSCs suppressor function and enhanced CIK activity against human HCC cell lines in vitro. 38…”

Section: Myeloid-derived Suppressor Cellsmentioning

confidence: 99%

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

Yu¹,

Greten²

2020

J Liver Cancer

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“…Other strategies targeting immunosuppressive cells have been tested in the preclinical setting. The FDA-approved MDSCs inhibitor Tadalafil may enhance the Cytokine-induced killer (CIK) cell-based immunotherapy in HCC patients [138].…”

Section: Preclinical Studies In Hcc Immunotherapymentioning

confidence: 99%

Inflammatory Mechanisms of HCC Development

Refolo

Messa

Guerra

et al. 2020

Cancers

141

105

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HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.

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“…The application of PDE5 inhibitors, including sildenafil, tadalafil, and vardenafil, can reduce the production of ARG1 and iNOS in MDSCs, abolish the inhibitory activity of MDSCs, reduce the number of T regs , and thus greatly delay the progression of tumors [87][88][89][90]. Treatment with tadalafil combined with cytokine-induced killer (CIK) cell-based immunotherapy enhanced CIK activity against human hepatocellular carcinoma (HCC) cell lines in vitro [91]. Nitroaspirin is another inhibitor of ARG1 and iNOS that reduces ROS generation [92].…”

Section: Inhibition Of Immunosuppressive Functionsmentioning

confidence: 99%

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

Wang

Jia

et al. 2020

Cancers

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Myeloid-derived suppressor cells (MDSCs), which are activated under pathological conditions, are a group of heterogeneous immature myeloid cells. MDSCs have potent capacities to support tumor growth via inhibition of the antitumoral immune response and/or the induction of immunosuppressive cells. In addition, multiple studies have demonstrated that MDSCs provide potential therapeutic targets for the elimination of immunosuppressive functions and the inhibition of tumor growth. The combination of targeting MDSCs and other therapeutic approaches has also demonstrated powerful antitumor effects. In this review, we summarize the characteristics of MDSCs in the tumor microenvironment (TME) and current strategies of cancer treatment by targeting MDSCs.

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Targeting the crosstalk between cytokine-induced killer cells and myeloid-derived suppressor cells in hepatocellular carcinoma

Cited by 115 publications

References 45 publications

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

Inflammatory Mechanisms of HCC Development

Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy

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