Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy

Zhou, Jingying; Liu, Man; Sun, Hanyong; Feng, Yuanming; Xu, Liangliang; Chan, Anthony W.H.; Tong, Joanna H.M.; Wong, John; Chong, Charing Ching‐Ning; Lai, Paul Bo San; Wang, Hector Kwong-Sang; Tsang, Shun-Wa; Goodwin, Tyler J.; Liu, Rihe; Huang, Leaf; Chen, Zhiwei; Sung, Joseph J.Y.; Chow, King Lau; To, Ka Fai; Cheng, Alfred S.L.

doi:10.1136/gutjnl-2017-314032

Cited by 156 publications

(171 citation statements)

References 50 publications

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“…MDSCs accounted for up to about 24% of total immune cells in the peripheral blood and 39% of total immune cells in the tumor. Further, we found that tumor‐infiltrating MDSCs exert potent CD8 + T‐cell suppression in HCC, which is consistent with previous studies …”

Section: Discussionsupporting

confidence: 93%

Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–Chemokine (C‐X‐C Motif) Receptor 2 Axis

Liu

Wang

et al. 2019

Hepatology

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Receptor‐interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid‐derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma–positive (IFN‐γ+) cluster of differentiation 8–positive (CD8+) tumor‐infiltrating lymphocytes (IFN‐γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C‐X‐C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1–chemokine (C‐X‐C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2‐induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1–CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.

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Section: Discussionsupporting

confidence: 93%

Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–Chemokine (C‐X‐C Motif) Receptor 2 Axis

Liu

Wang

et al. 2019

Hepatology

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“…Emerging evidence highlights the key roles of CDKs in tumor immunity, especially CDK20. Activation of CDK20 leads to accumulation of polymorphonuclear myeloid‐derived suppressor cells and impairs antitumor immunity in mice through the nuclear factor‐κB/interleukin‐6‐dependent pathway . Inhibition of CDK20 combined with tumor immunology could develop novel treatment options for HCC …”

Section: Biology and Regulation Of Cdks In Hccmentioning

confidence: 99%

“…Activation of CDK20 leads to accumulation of polymorphonuclear myeloid-derived suppressor cells and impairs antitumor immunity in mice through the nuclear factor-κB/interleukin-6-dependent pathway. 31 Inhibition of CDK20 combined with tumor immunology could develop novel treatment options for HCC. 31,37 Other CDKs Most CDKs are important in regulating cellular functions and tumorigenesis.…”

Section: Cyclin-dependent Kinase 20mentioning

confidence: 99%

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Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Shen

Dean²,

et al. 2019

Hepatology Research

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Liver cancer is the fourth leading cause of cancer related mortality in the world, with hepatocellular carcinoma (HCC) representing the most common primary subtype. Two‐thirds of HCC patients have advanced disease when diagnosed, and for these patients, treatment strategies remain limited. In addition, there is a high incidence of tumor recurrence after surgical resection with the current treatment regimens. The development of novel and more effective agents is required. Cyclin‐dependent kinases (CDKs) constitute a family of 21 different protein kinases involved in regulating cell proliferation, apoptosis, and drug resistance, and are evaluated in preclinical and clinical trials as chemotherapeutics. To summarize and discuss the therapeutic potential of targeting CDKs in HCC, recent published articles identified from PubMed were comprehensively reviewed. The key words included hepatocellular carcinoma, cyclin‐dependent kinases, and CDK inhibitors. This review focuses on the emerging evidence from studies describing the genetic and functional aspects of CDKs in HCC. We also present an overview of CDK inhibitors that have shown efficacy in laboratory studies of HCC. Although many of the studies assessing CDK‐targeting therapies in HCC are at the preclinical stage, there is significant evidence that CDK inhibitors used alone or in combination with established chemotherapy drugs could have significant applications in HCC.

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“…recently reported that the potent suppression activity of tumor‐infiltrating CD11b + CD33 + HLA‐DR ‐ myeloid cells in hepatocellular carcinoma patients was effectively abrogated by blocking cell cycle‐related kinase . This effect was accompanied by increased tumor‐infiltration of effector T cells and upregulation of intratumoral PD‐L1 expression that can improve the efficacy of anti‐PD‐L1 therapy . Moreover, blockade of cyclooxygenase‐2 (COX‐2), a key enzyme in MDSC suppressive characteristics, resulted in limiting the ability of MDSC to suppress T‐cell function .…”

Section: Effects Of Targeting Mdsc and Immune Checkpoint Inhibitors Omentioning

confidence: 99%

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

Toor

Elkord

2018

Immunol Cell Biol

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Immune evasion is a characteristic of most human malignancies and is induced via various mechanisms. Immunosuppressive cells, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), are key mediators in assisting tumors to escape immune surveillance. Expansion of MDSC, Treg and elevated levels of immune checkpoints (IC) are frequently detected in the tumor microenvironment and periphery of cancer patients. Various therapeutic agents have been shown to target MDSC and to block IC for inducing anti-tumor immunity and reversal of tumor immune escape. Importantly, some recent studies have shown that MDSC targeting improves the efficacy of IC blockade in cancer therapy. However, there is a pressing need to improve our understanding of the distinct role of these cells to develop combination therapy that attacks tumor cells from all frontiers to improve cancer therapeutics. Herein, we discuss the role of MDSC in cancer progression, interactions with IC in the context of anti-cancer immunity and the current therapeutic strategies to target MDSC and block IC in cancer.

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Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy

Abstract: Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.

Cited by 156 publications

References 50 publications

Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–Chemokine (C‐X‐C Motif) Receptor 2 Axis

Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–Chemokine (C‐X‐C Motif) Receptor 2 Axis

Role of cyclin‐dependent kinases (CDKs) in hepatocellular carcinoma: Therapeutic potential of targeting the CDK signaling pathway

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

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