In a lung tumor model, a complex of IL2/anti-IL2 (IL2Cx, which directs IL2 to NK and CD8+ T cells but not Tregs) and anti-PD-1 controlled tumor growth better than either monotherapy. In a B16F10-OVA melanoma model, IL2Cx delayed tumor growth, and this effect was boosted by either anti-CTLA-4 or anti-PD-1/PD-L1. CD8+ T cell infiltration, neoepitope-specific responses, and reinvigoration were increased by IL2Cx alone, and more so in combination treatments. The antitumor effect of both combinations was dependent on CD8+ T cells, and the effect of IL2Cx/anti-CTLA-4 was also dependent on NK cells, potentiated by Treg depletion.
High-dose IL2 immunotherapy can induce long-lasting cancer regression but is toxic and insufficiently efficacious. Improvements are obtained with IL2/anti-IL2 complexes (IL2Cx) which re-direct IL2 action to CD8+ T and NK cells. Here, we evaluated the efficacy of combining IL2Cx with blockade of inhibitory immune pathways. In an autochthonous lung adenocarcinoma model, we show that the IL2Cx/anti-PD-1 combination increases CD8+ T-cell infiltration of the lung and controls tumor growth. In the B16-OVA model, which is resistant to checkpoint inhibition, combination of IL2Cx with PD-1 or CTLA-4 pathway blockade reverses that resistance. Both combinations work by reinvigorating exhausted intratumoral CD8+ T cells and by increasing the breadth of tumor-specific T-cell responses. However, only the IL2Cx/anti-CTLA-4 combination is able to rescue NK cell antitumor function by modulating intratumoral regulatory T cells. Overall, association of IL2Cx with PD-1 or CTLA-4 pathway blockade acts by different cellular mechanisms, paving the way for the rational design of combinatorial antitumor therapies.
Author Info: (1) U932-Translational Immunotherapy team, Research Center, PSL Research University, INSERM U932, Institut Curie, F-75005. (2) SiRIC TransImm <<Translational Immunotherapy Team>>,
Author Info: (1) U932-Translational Immunotherapy team, Research Center, PSL Research University, INSERM U932, Institut Curie, F-75005. (2) SiRIC TransImm <<Translational Immunotherapy Team>>, Translational Research Department, Research Center, PSL Research University, INSERM U932, Institut Curie, F-75005. (3) U932-Translational Immunotherapy team, Research Center, PSL Research University, INSERM U932, Institut Curie, F-75005. (4) U932-Translational Immunotherapy team, Institute Curie. (5) U932-Translational Immunotherapy team, Institute Curie. (6) U932-Innate like and CD4+ T cells in cancer, Institute Curie. (7) INSERM U932, Institute Curie. (8) U932-Innate like and CD4+ T cells in cancer, Institute Curie. (9) SiRIC TransImm <<Translational Immunotherapy Team>>, Translational Research Department, Centre d'Investigation Clinique Biotherapie, Research Center - Institut Curie,PSL Research University, INSERM U932, F-75005. (10) SiRIC TransImm <<Translational Immunotherapy Team>>, Translational Research Department, Research Center, PSL Research University, INSERM U932, Institut Curie, F-75005 eliane.piaggio@curie.fr.
