| 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
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| 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
|
| リソース情報 |
| ヒト・動物細胞 |
SSP-25(RCB1293), RBE(RCB1292) |
