論文 - 詳細
| RRC ID | 68865 |
|---|---|
| 著者 | Chui NN, Cheu JW, Yuen VW, Chiu DK, Goh CC, Lee D, Zhang MS, Ng IO, Wong CC. |
| タイトル | Inhibition of CMTM4 Sensitizes Cholangiocarcinoma and Hepatocellular Carcinoma to T Cell-Mediated Antitumor Immunity Through PD-L1. |
| ジャーナル | Hepatol Commun |
| Abstract |
Liver cancers consist primarily of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Immune checkpoint inhibitors have emerged as promising therapeutic agents against liver cancers. Programmed cell death protein 1 (PD-1) is an immunoinhibitory receptor present on T cells that interacts with its ligand programmed death-ligand 1 (PD-L1) found on cancer cells. Blocking PD-1/PD-L1 binding improves T-cell survival, proliferation and cytotoxicity, which enhances their antitumor activity. Better understanding of the molecular mechanisms governing PD-1/PD-L1 response is essential to the development of predictive markers and therapeutic combinations that could improve the efficiency of anti-PD-1/PD-L1 treatment. Chemokine-like factor (CKLF)-like MARVEL transmembrane domain-containing 6 (CMTM6) has been recently identified as a major regulator of PD-L1. Another member in the CMTM family, CKLF-like MARVEL transmembrane domain-containing 4 (CMTM4), has been shown to compensate for the effects of CMTM6 when CMTM6 is lost. Interestingly, we found that CMTM4 is the major regulator of PD-L1 in the context of liver cancer. Up-regulated CMTM4 in patients with HCC and ICC is associated with poor patient survival, potentially due to its function in stabilizing PD-L1 expression, hence facilitating escape from T cell-mediated cytotoxicity. We confirmed the role of CMTM4 as a positive regulator of PD-L1 in multiple HCC and ICC cell lines and demonstrated that CMTM4 stabilizes PD-L1 through posttranslational mechanisms. In vivo, suppression of Cmtm4 inhibited HCC growth and increased CD8+ T-cell infiltration in immunocompetent mice. Furthermore, we found that depletion of CMTM4 sensitized HCC tumor to anti-PD-L1 treatment compared with control. This suggests that CMTM4 expression level could be a predictive marker for patient response to anti-PD-L1 treatment, and CMTM4 depletion can potentially be used to enhance the clinical benefits of anti-PD-L1 immunotherapy in patients with liver cancer. |
| 巻・号 | 6(1) |
| ページ | 178-193 |
| 公開日 | 2022-1-1 |
| DOI | 10.1002/hep4.1682 |
| PMID | 34558800 |
| PMC | PMC8710793 |
| MeSH | Animals Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / immunology* Carcinoma, Hepatocellular / metabolism Cells, Cultured Cholangiocarcinoma / drug therapy Cholangiocarcinoma / immunology* Cholangiocarcinoma / metabolism Hepatocytes Humans Immune Checkpoint Inhibitors / therapeutic use Liver Neoplasms / drug therapy Liver Neoplasms / immunology* Liver Neoplasms / metabolism MARVEL Domain-Containing Proteins / antagonists & inhibitors MARVEL Domain-Containing Proteins / genetics* Mice, Inbred C57BL Programmed Cell Death 1 Receptor / antagonists & inhibitors Programmed Cell Death 1 Receptor / immunology* Up-Regulation |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 7 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | SSP-25(RCB1293), RBE(RCB1292) |