Cisplatin enhances NK cells immunotherapy efficacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals

Abstract

The aim of this study is to investigate the influence of cisplatin on the efficacy of natural killer (NK) cells immunotherapy to suppress HCC progression, and provide valuable information on better application of cisplatin in clinical settings. By using in vitro cell cytotoxicity test and in vivo liver orthotopic xenograft mice model, we identified the role of cisplatin in modulating NK cells cytotoxicity. Luciferase report assay and chromatin immunoprecipitation assay were applied for mechanism dissection. Immunohistochemistry was performed for sample staining. We found cisplatin could enhance the efficacy of NK cell immunotherapy to better suppress HCC progression via altering the androgen receptor (AR)-UL16-binding protein 2 (ULBP2) signals both in vitro and in vivo. Mechanism dissection revealed that cisplatin could suppress AR expression via two distinct ways: increasing miR-34a-5p to suppress AR expression and altering the ubiquitination to accelerate the AR protein degradation. The suppressed AR might then function through up-regulating ULBP2, a natural-killer group 2 member D ligand, to enhance the cytotoxicity of NK cells. Together, these results indicated an unrecognized favoring effect of cisplatin in HCC treatment. By suppressing AR in HCC, cisplatin could up-regulate cytotoxicity of NK cells to better target HCC. This finding may provide a potential new approach to control HCC by combining traditional chemotherapy with immunotherapy.

Inhibition of IL‐6‐JAK/Stat3 signaling in castration‐resistant prostate cancer cells enhances the NK cell‐mediated cytotoxicity via alteration of PD‐L1/NKG2D ligand levels

“…NK cell cytotoxicities to C4‐2siIL‐6/sc and CWRsiIL‐6/sc cells were then tested. To monitor NK cell‐mediated cytotoxicity, two different assays, the lactate dehydrogenase (LDH) release‐based NK cytotoxicity test (Decker and Lohmann‐Matthes, ; Korzeniewski and Callewaert, ; Shi et al ., ; Smith et al ., ) and the colony formation assay (Rong et al ., ), were used. In these experiments, two NK cell sources established NK92 cell line that was known to exhibit high NK cytotoxicity and has been widely used in in vitro and in mouse studies (Klingemann et al ., ; Tam et al ., ), and primary NK cells that were isolated from the peripheral blood mononuclear cells (PBMCs) of healthy donors via magnetic beads isolation method, were used.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…[270][271][272] However, it is uncertain whether that combination with immunotherapy and NTDDS can induce synergistic effect of anti-HCC. Furthermore, the high expression of MDR results in the poor response of HCC to chemotherapy.…”

Cisplatin plus norcantharidin alter the expression of TGF-β1/Smads signaling pathway in hepatocellular carcinoma

“…DDP has been widely used i n the treatment of different kinds of cancers, especially in the treatment of HCC (5-7). DDP can enhance NK cells immunotherapeutic effi cacy to suppress HCC progression via altering the androgen receptor (AR)-ULBP2 signals (20). DDP also inhibits transcription activity of NF-κB and increases apoptosis in human hepatocellular carcinoma cells (21).…”