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

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.

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.

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.

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.