Lenalidomide Induces Interleukin-21 Production by T Cells and Enhances IL21-Mediated Cytotoxicity in Chronic Lymphocytic Leukemia B Cells

Abstract

The immunomodulatory drug lenalidomide has demonstrated efficacy in chronic lymphocytic leukemia (CLL) patients, despite a lack of direct cytotoxic effect in vitro. The mechanism of lenalidomide efficacy in vivo is thought to occur via a combination of enhanced immune activity and an alteration of tumor cell–microenvironment interactions. We demonstrate in whole blood from CLL patients that lenalidomide significantly depletes malignant B cells. Lenalidomide also induced production of interleukin-21 (IL21) and its mRNA in T cells from CLL patients. Lenalidomide also enhanced upregulation of functional IL21 receptor (IL21R) on the cell surface and increased receptor mRNA in vitro. The in vitro combination of IL21 and lenalidomide enhanced IL21-mediated cytotoxicity toward CLL cells through a variety of mechanisms. We show association of cell death with upregulation of Bid by IL21, enhanced upregulation of Bid by the combination therapy, and diminished Lck and downstream BCR signaling activation of Syk and PLCG2. Collectively, we demonstrated an immune cell–tumor cell interaction through lenalidomide-mediated induction of IL21 and IL21R, with enhanced IL21-mediated cytotoxicity, which provides justification for this combination in clinical trials for CLL patients.

IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner

“…Furthermore, we were interested if we could see similar effects concerning redox capacities in CLL patient-derived T-cells that were already challenged by their ROS-rich environment. Although IL-21 serum levels are not found reduced in CLL patients (as compared to healthy controls) ( Supplementary Figure 2D ), recent studies indicate that promoting the IL-21 production might have a beneficial impact in terms of CLL-cell-directed cytotoxicity [ 25 ]. Indeed, we observed decreased mitochondrial and total cellular ROS-levels in T-cells from CLL PBMCs cultured with IL-21 (Figure 2G ).…”

Antithymocyte Globulin Antibody Titer Congruent With Kidney Transplantation: Analysis of Incidence, Outcomes, Cost, and Alternative Targets

“…For example, studies have shown that increased IL-21 in T cells enhances cell cytotoxicity. 45 Moreover, IL-21 is also increased in other immune-mediated pathologies such as osteoarthritis. 17 However, IL-21 and CD40L levels are known to be unaffected by standard triple maintenance immunosuppression (calcineurin inhibitors + mycophenolate mofetil + steroids) typically used following renal transplant.…”

Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance)

“…In addition, lenalidomide mediates degradation of IKZF1 and IKZF3, both transcription factors expressed in T cells as well as in CLL cells. 40,41 IKZF3 has recently been shown to be mutated in a small subset of CLL patients, and is over-expressed in the majority of CLL patients, suggesting a role in CLL pathogenesis. 5 IKZF3 disrupts apoptosis, possibly through promoting upregulation of bcl-2 family proteins.…”

“…Among the 400 patients analyzed, 144 (36%) were at least 65 years old. In this subgroup of patients, the CR rate was 38% (95% CI, [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] and the ORR was 66% (95% CI, 58-74).…”