| RRC ID |
66854
|
| 著者 |
Sugihara E, Hashimoto N, Osuka S, Shimizu T, Ueno S, Okazaki S, Yaguchi T, Kawakami Y, Kosaki K, Sato TA, Okamoto S, Saya H.
|
| タイトル |
The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.
|
| ジャーナル |
Cancer Res
|
| Abstract |
Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.
|
| 巻・号 |
80(20)
|
| ページ |
4439-4450
|
| 公開日 |
2020-10-15
|
| DOI |
10.1158/0008-5472.CAN-19-3993
|
| PII |
0008-5472.CAN-19-3993
|
| PMID |
32928920
|
| MeSH |
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / immunology*
Adolescent
Adult
Aged
Aged, 80 and over
Animals
CD40 Antigens / immunology
CD40 Antigens / metabolism
Cell Line, Tumor
Cell Survival
Child
Child, Preschool
Cytotoxicity, Immunologic
Female
Humans
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / immunology*
Lymphoma, Large B-Cell, Diffuse / genetics
Lymphoma, Large B-Cell, Diffuse / immunology*
Lymphoma, Large B-Cell, Diffuse / mortality
Lymphoma, Large B-Cell, Diffuse / pathology*
Male
Mice
Mice, Inbred C57BL
Middle Aged
NIH 3T3 Cells
Neoplasm Proteins / genetics
Neoplasm Proteins / immunology*
Neoplasms, Experimental / pathology
Xenograft Model Antitumor Assays
Young Adult
fas Receptor / genetics
fas Receptor / immunology*
fas Receptor / metabolism
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
NIH3T3 |
