The inhibitor of apoptosis protein livin confers resistance to fas-mediated immune cytotoxicity in refractory lymphoma

Eiji Sugihara, Norisato Hashimoto, Satoru Osuka, Takatsune Shimizu, Sayaka Ueno, Shogo Okazaki, Tomonori Yaguchi, Yutaka Kawakami, Kenjiro Kosaki, Taka Aki Sato, Shinichiro Okamoto, Hideyuki Saya

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4439-4450
Number of pages12
JournalCancer Research
Volume80
Issue number20
DOIs
Publication statusPublished - 15-10-2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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