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Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes.

ABSTRACT: One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors to HCC development in a T cell-dependent or non-dependent manner. Clinically, the frequency of MDSCs is firmly linked to HCC clinical outcomes and the effectiveness of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs). Furthermore, MDSCs can also be used as prognostic and predictive biomarkers for patients with HCC. Therefore, treatments reprograming MDSCs may offer potential therapeutic opportunities in HCC. Here, we recapitulated the dynamic relevance of MDSCs in the initiation and development of HCC and paid special attention to the effect of MDSCs on T cells infiltration in HCC. Finally, we pointed out the potential therapeutic effect of targeting MDSCs alone or in combination, hoping to provide new insights into HCC treatment.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8534227 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes.

Wang Yijun Y Zhang Tongyue T Sun Mengyu M Ji Xiaoyu X Xie Meng M Huang Wenjie W Xia Limin L

Cancers 20211013 20

One of the major challenges in hepatocellular carcinoma (HCC) treatment is drug resistance and low responsiveness to systemic therapies, partly due to insufficient T cell infiltration. Myeloid-derived suppressor cells (MDSCs) are immature marrow-derived cell populations with heterogeneity and immunosuppression characteristics and are essential components of the suppressive tumor immune microenvironment (TIME). Increasing evidence has demonstrated that MDSCs are indispensable contributing factors ...[more]

PMID: 34680276

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Project description:Background & aimsCytokine-induced killer (CIK) cell-based immunotherapy is effective as an adjuvant therapy in early stage hepatocellular carcinoma (HCC) but lacks efficacy in advanced HCC. We aimed to investigate immune suppressor mechanisms in HCC, focusing on the role of myeloid-derived suppressor cells (MDSCs) in response to CIK therapy.MethodsMDSCs were quantified by flow cytometry and quantitative real-time PCR. Cytokines were detected by cytokine array. A lactate dehydrogenase cytotoxicity assay was performed in the presence or absence of MDSCs to study CIK function against HCC cells in vitro. An FDA-approved PDE5 inhibitor, tadalafil, was used to target MDSCs in vitro and in vivo. Two different murine HCC cell lines were tested in subcutaneous and orthotopic tumor models in C57BL/6 and BALB/c mice. The antitumor effects of human CIKs and MDSCs were also tested in vitro.ResultsAdoptive cell transfer of CIKs into tumor-bearing mice induced inflammatory mediators (e.g., CX3CL1, IL-13) in the tumor microenvironment and an increase of tumor-infiltrating MDSCs, leading to impaired antitumor activity in 2 different HCC models. MDSCs efficiently suppressed the cytotoxic activity of CIKs in vitro. In contrast, treatment with a PDE5 inhibitor reversed the MDSC suppressor function via ARG1 and iNOS blockade and systemic treatment with a PDE5 inhibitor prevented MDSC accumulation in the tumor microenvironment upon CIK cell therapy and increased its antitumor efficacy. Similar results were observed when human CIKs were tested in vitro in the presence of CD14+HLA-DR-/low MDSCs. Treatment of MDSCs with a PDE5 inhibitor suppressed MDSC suppressor function and enhanced CIK activity against human HCC cell lines in vitro.ConclusionOur results suggest that targeting MDSCs is an efficient strategy to enhance the antitumor efficacy of CIKs for the treatment of patients with HCC.Lay summaryCytokine-induced killer cells are a mixture of immune cells given to eliminate cancer cells. However, not all patients respond to this treatment. Herein, we show in 2 different liver cancer models that myeloid-derived suppressor cells are increased in response to cytokine-induced killer cell therapy. Targeting these myeloid-derived suppressor cells may provide an additional therapeutic benefit alongside cytokine-induced killer cell therapy.

Dataset Information

Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes.

Publications

Therapeutic Values of Myeloid-Derived Suppressor Cells in Hepatocellular Carcinoma: Facts and Hopes.

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