Efficient recruitment of c‐FLIP(L) to the death‐inducing signaling complex leads to Fas resistance in natural killer‐cell lymphoma

Activation‐induced cell death (AICD) mediated by the Fas/Fas ligand (FasL) system plays a key role in regulating immune response. Although normal natural killer (NK) cells use this system for their homeostasis, malignant NK cells seem to disrupt the process. Extranodal NK/T‐cell lymphoma, nasal type (ENKL) is a rare but fatal disease, for which novel therapeutic targets need to be identified. We confirmed that ENKL‐derived NK cell lines NK‐YS and Hank1, and primary lymphoma cells expressed procaspase‐8/FADD‐like interleukin‐1β‐converting enzyme (FLICE) modulator and cellular FLICE‐inhibitory protein (c‐FLIP), along with Fas and FasL. Compared with Fas‐sensitive Jurkat cells, NK‐YS and Hank1 showed resistance to Fas‐mediated apoptosis in spite of the same expression levels of c‐FLIP and the death‐inducing signaling complex (DISC) formation. Unexpectedly, the long isoform of c‐FLIP (c‐FLIP(L)) was coimmunoprecipitated with Fas predominantly in both ENKL‐derived NK cell lines after Fas ligation. Indeed, c‐FLIP(L) was more sufficiently recruited to the DISC in both ENKL‐derived NK cell lines than in Jurkat cells after Fas ligation. Knockdown of c‐FLIP(L) per se enhanced autonomous cell death and restored the sensitivity to Fas in both NK‐YS and Hank1 cells. Although ENKL cells are primed for AICD, they constitutively express and efficiently utilize c‐FLIP(L), which prevents their Fas‐mediated apoptosis. Our results show that c‐FLIP(L) could be a promising therapeutic target against ENKL.