RRC ID 66854
Author Sugihara E, Hashimoto N, Osuka S, Shimizu T, Ueno S, Okazaki S, Yaguchi T, Kawakami Y, Kosaki K, Sato TA, Okamoto S, Saya H.
Title The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.
Journal 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.
Volume 80(20)
Pages 4439-4450
Published 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
Human and Animal Cells NIH3T3