Abstract : While patient selection and clinical management have reduced high-dose IL-2 (HDIL2) immunotherapy toxicities, the immune mechanisms that underlie HDIL2-induced morbidity remain unclear. Here we show that dose-dependent morbidity and mortality of IL-2 immu-notherapy can be modeled in human immune system (HIS) mice. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. Preferential expansion of effector T cells secondary to defective suppressive capacity of regulatory T (T reg) cells after HDIL2 therapy further underscores the importance of T reg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of T reg after LDIL2 therapy, and is ameliorated in HDIL2-treated HIS mice receiving the PIM-1 kinase inhibitor, Kaempferol. Modeling IL-2 pathophysiology in HIS mice offers a means to understand the functions of effector and regulatory T cells in immune-mediated toxicities associated with cancer immunotherapy.
https://hal-pasteur.archives-ouvertes.fr/pasteur-01663992
Contributeur : Marie-Luce Kop
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Soumis le : jeudi 14 décembre 2017 - 14:13:09
Dernière modification le : mercredi 17 octobre 2018 - 12:42:06
Yan Li, Helene Strick-Marchand, Ai Lim, Jiazi Ren, Guillemette Masse-Ranson, et al.. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nature Communications, Nature Publishing Group, 2017, 8 (1), pp.1762. 〈10.1038/s41467-017-01570-9〉. 〈pasteur-01663992〉
