IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro

Abstract

Interleukin-21 (IL-21

Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab

“…The delicate balance between various family members, including Bcl-2, Noxa, Bim, and others, determines CLL cell fate. [1][2][3][4] Myeloid cell leukemia-1 (Mcl-1) is a particularly intriguing member of this family that interacts with multiple other Bcl-2 family proteins and is dynamically regulated at both the mRNA and protein level. Mcl-1 modulation impacts response of CLL cells to various commonly used therapeutic agents, and loss of Mcl-1 is by itself sufficient to induce apoptosis in CLL cells.…”

Anti-CD20-interleukin-21 fusokine targets malignant B cells via direct apoptosis and NK-cell–dependent cytotoxicity

“…[26][27][28][29][30][31] We and others recently showed that IL-21 enhances rituximab-mediated ADCC of NHL cells, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemias. 20,32,33 Similarly, increased ADCC was also observed in a murine breast cancer model treated with the anti-HER2 Ab (trastuzumab) and IL-21. 21,34 Apart from its immunostimulatory effects, IL-21 exerts direct cytotoxicity on a variety of IL-21R-expressing NHLs, including diffuse large B-cell lymphoma (DLBCL), MCL, chronic lymphocytic leukemia, and follicular lymphoma.…”

“…To compare the efficacy of the fusokine to native IL-21, we selected an IL-21 dose that led to maximal killing (50 ng/mL), based on our prior studies and reports in the literature. 20,35 Cells were exposed to equimolar doses of the aCD20-IL-21 fusokine and IL-21. aCD20-IL-21 induced nearly equivalent or slightly higher cell death compared with native IL-21 or its combination with the parental Ab, suggesting its biological activity is retained (Figure 2A; supplemental Figure 3A).…”

“…[16][17][18][19] Strategies combining mAbs with cytokines stimulating effector cells have also been attempted to enhance ADCC activity. 13,[20][21][22][23] Interleukin-21 (IL-21), a member of the IL-2 cytokine family, is a potent immunostimulatory cytokine exhibiting diverse regulatory effects on NK, T, and B cells. 24,25 IL-21 possesses antitumor activity against a variety of cancers not expressing IL-21 receptor (IL-21R) through activation of the immune system.…”

L’interleukine-21, un nouvel adjuvant contre le cancer ?

“…Non seulement l'IL-21 active la réponse anti-tumorale relayée par les cellules NK et les LTCD8 + , mais, de plus, elle peut aussi avoir un effet anti-tumoral direct sur les cellules cancéreuses de type lymphocytaire. L'IL-21 induit l'apoptose de cellules de leucémie lymphocytaire chronique (LLC) et augmente l'efficacité de l'ADCC en présence du Rituximab [11]. Cette cytokine provoque l'apoptose de cellules provenant de lymphomes B non-hodgkiniens (LCBNH), réduit la prolifération de cellules de lymphomes diffus à grandes cellules B (LDGCB) et déclenche l'apoptose des cellules primaires de lymphomes de types LLC et LDGCB [12,13].…”