TY - JOUR
T1 - The inhibitor of apoptosis protein livin confers resistance to fas-mediated immune cytotoxicity in refractory lymphoma
AU - Sugihara, Eiji
AU - Hashimoto, Norisato
AU - Osuka, Satoru
AU - Shimizu, Takatsune
AU - Ueno, Sayaka
AU - Okazaki, Shogo
AU - Yaguchi, Tomonori
AU - Kawakami, Yutaka
AU - Kosaki, Kenjiro
AU - Sato, Taka Aki
AU - Okamoto, Shinichiro
AU - Saya, Hideyuki
N1 - Funding Information:
We thank T. Kitamura (The University of Tokyo, Tokyo, Japan) for providing the vectors pMXs-IRES-GFP and -puro as well as Plat-E cells; S. Yamanaka (Kyoto University, Kyoto, Japan) for providing pLenti6/UbC/V5-DEST-Slc7a1; M. Yonezawa, I. Ishimatsu, S. Hayashi, N. Kamoshita, and K. Sonoda for technical assistance; and K. Arai, M. Sato, and M. Kobori for help with preparation of the manuscript. This work was supported by Japan Society for the Promotion of Science KAKENHI grants 15K14384 (to H. Saya) and 15K06840 (to E. Sugihara) as well as by a Keio University Grant-in-Aid for Encouragement of Young Medical Scientists (to E. Sugihara).
Funding Information:
E. Sugihara reports grants from Japan Society for the Promotion of Science, Japanese Society of Hematology, and grants from Japan Leukemia Research Fund during the conduct of the study. T. Yaguchi reports grants from Ono Pharmaceutical Co. Ltd., Carna Biosciences, Inc., Kowa Company, Ltd., and nonfinancial support from JSR Corporation outside the submitted work. Y. Kawakami reports grants and personal fees from Ono Pharmaceutical Co. and Bristol-Myers Squibb, personal fees from MSD, AstraZeneca, Chugai, Taiho Pharma, grants from CarnaBioSciences, and grants and nonfinancial support from JSR outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/10/15
Y1 - 2021/10/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-3993
DO - 10.1158/0008-5472.CAN-19-3993
M3 - Article
C2 - 32928920
AN - SCOPUS:85100399919
SN - 0008-5472
VL - 80
SP - 4439
EP - 4450
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -
