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Cancer Immunol Res. 2019 Mar;7(3):443-457. doi: 10.1158/2326-6066.CIR-18-0697. Epub 2019 Jan 16.

IL2/Anti-IL2 Complex Combined with CTLA-4, But Not PD-1, Blockade Rescues Antitumor NK Cell Function by Regulatory T-cell Modulation.

Author information

1
Institut Curie, PSL Research University, INSERM U932, TransImm Team, Paris, France.
2
Institut Curie, PSL Research University, Clinical Immunology Laboratory, Paris, France.
3
Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris, France.
4
Institut Curie, PSL Research University, INSERM U932, TransImm Team, Paris, France. eliane.piaggio@curie.fr.

Abstract

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 redirect IL2 action to CD8+ T and natural killer (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.

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