High IL‐10 levels during CRS are negatively associated with NK‐cell recovery after CAR‐T cell therapy

Abstract

Abstract Objectives Immune reconstitution following chimeric antigen receptor (CAR)‐T cell therapy remains a critical clinical challenge, and the determinants of natural killer (NK)‐cell recovery are not fully understood. Methods We longitudinally monitored natural killer (NK)‐cell recovery in 64 patients during the first year after CD19‐directed CAR‐T cell therapy, analysing NK‐cell counts and surface receptor expression. Associations between cytokine release syndrome (CRS), cytokine profiles, and NK‐cell numerical reconstitution were evaluated, and mechanistic insights were explored using in vitro NK‐cell assays. Results NK‐cell numerical and phenotypic recovery was impaired within the first month after CAR‐T cell infusion. Notably, NK‐cell numerical recovery was significantly delayed in patients who developed CRS. A reduced NK‐to‐T cell ratio at one‐month post‐infusion was associated with a markedly increased risk of viral infection (hazard ratio = 4.512). Elevated interleukin (IL)‐10 levels during CRS were inversely associated with NK‐cell recovery. Patients with high IL‐10 levels exhibited delayed NK‐cell reconstitution, which was independently validated in two external cohorts. Mechanistically, in vitro exposure of NK cells to IL‐10 promoted caspase‐3 activation, increased apoptosis, and enhanced reactive oxygen species accumulation and lipid peroxidation. Rescue experiments using ferrostatin‐1 and Z‐VAD‐FMK further supported the involvement of IL‐10 in apoptosis and ferroptosis. Conclusion These findings highlight a previously underappreciated role of IL‐10 in shaping NK‐cell reconstitution post‐CAR‐T cell therapy, particularly in the setting of CRS. Patients with CRS accompanied by elevated IL‐10 levels may benefit from anti‐inflammatory interventions or therapeutic strategies aimed at promoting NK‐cell recovery.