IL2/Anti-IL2 complex combined with CTLA-4, But Not PD-1, blockade rescues antitumor NK cell function by regulatory T-cell Modulation

Abstract

High-dose IL2 immunotherapy can induce long-lasting tion of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses cancer regression but is toxic and insufficiently efficacious. that resistance. Both combinations work by reinvigorating Improvements are obtained with IL2/anti-IL2 complexes exhausted intratumoral CD8 þ T cells and by increasing the (IL2Cx), which redirect IL2 action to CD8 þ T and natural breadth of tumor-specific T-cell responses. However, only the killer (NK) cells. Here, we evaluated the efficacy of combining IL2Cx/anti–CTLA-4 combination is able to rescue NK cell IL2Cx with blockade of inhibitory immune pathways. In an antitumor function by modulating intratumoral regulatory autochthonous lung adenocarcinoma model, we show that T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 the IL2Cx/anti–PD-1 combination increases CD8 þ T-cell infil-pathway blockade acts by different cellular mechanisms, pav-tration of the lung and controls tumor growth. In the B16-OVA ing the way for the rational design of combinatorial antitumor model, which is resistant to checkpoint inhibition, combina-therapies.