Regulatory T cells control toxicity in a humanized model of IL-2 therapy

Yan Li,Helene Strick-Marchand,Bin Li Bin Li,Dan Li Dan Li,James P Di Santo,Gregory Jouvion,Sophie Lucas,Ai Ing Lim,Jiazi Ren,Lars Rogge,Guillemette Masse-Ranson

doi:10.1038/s41467-017-01570-9

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 immunotherapy 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 (Treg) cells after HDIL2 therapy further underscores the importance of Treg in the maintenance of immune tolerance. IL-2 toxicity is induced by selective depletion or inhibition of Treg 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.

Highlights

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
Our ability to study HDIL2-mediated toxicity in the clinical setting is limited for several reasons: first, criteria for toxicity evaluation and specifics of administration practices of HDIL2 therapy vary in different centers[8]; second, ethical and safety concerns restrict measurements and treatments allowed for patients undergoing HDIL2; third, therapeutic agents used before and during the HDIL2 therapy for each patient could complicate the toxic effect of IL-2, making the comparison between different patients difficult[9]
A major recent advance in the treatment of human cancer involves the therapeutic targeting of immune response ‘checkpoints’ via antibodies that interfere with cytotoxic T lymphocyteassociated antigen (CTLA)-4 and programmed cell death (PD)-1 receptors and their ligands

Summary

Introduction

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. Depletion of human T cell subsets during the HDIL2 treatment reduces toxicity, pointing to the central function of T cells. 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. Lung endothelial cells were shown to express a functional IL-2 receptor, suggesting their role in VLS initiation[15]. These studies suggest a complex etiology for VLS with the potential participation of both haematopoietic and non-haematopoietic cellular targets that create a toxic cytokine ‘milleu’ with elevated TNF and IFN-γ16,17

Methods

Results

Conclusion