1. An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion
- Author
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Maria-Sophia Vidali, Louis Boon, Aggelos Banos, Aikaterini Termentzi, Triantafyllos Chavakis, Maren Köhne, Panayotis Verginis, Vasiliki Koliaraki, Aikaterini Hatzioannou, Dimitrios T. Boumpas, Constantinos Fedonidis, Marc Beyer, Theodore Sakelaropoulos, Jerome Zoidakis, Ana Henriques, Panagiotis Georgiadis, Aristotelis Tsirigos, and Kristian Händler
- Subjects
0301 basic medicine ,metabolism [Interleukin-1 Receptor-Like 1 Protein] ,immunology [Tumor Escape] ,medicine.medical_treatment ,Immunology ,Il33 protein, mouse ,chemical and pharmacologic phenomena ,Biology ,medicine.disease_cause ,immunology [Melanoma, Experimental] ,genetics [Interleukin-33] ,Autoimmunity ,Mice ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,immunology [Interferon-gamma] ,Cancer immunotherapy ,Interferon ,Cell Line, Tumor ,medicine ,Animals ,Immunology and Allergy ,ddc:610 ,Receptor ,Mice, Knockout ,NF-kappa B ,Interleukin ,hemic and immune systems ,Il1rl1 protein, mouse ,Immunotherapy ,Interleukin-33 ,Interleukin-1 Receptor-Like 1 Protein ,3. Good health ,Chromatin ,Mice, Inbred C57BL ,Interleukin 33 ,030104 developmental biology ,genetics [Interferon-gamma] ,Cancer research ,metabolism [NF-kappa B] ,immunology [Interleukin-33] ,immunology [T-Lymphocytes, Regulatory] ,030215 immunology ,medicine.drug - Abstract
Regulatory T (Treg) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of Treg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide Treg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of Treg cells. Specifically, IL-33-deficient Treg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion. On activation, Il33-/- Treg cells exhibited epigenetic re-programming with increased chromatin accessibility of the Ifng locus, leading to elevated interferon (IFN)-γ production in a nuclear factor (NF)-κB-T-bet-dependent manner. IFN-γ was essential for Treg cell defective function because its ablation restored Il33-/- Treg cell-suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a new and therapeutically important intrinsic role of IL-33 in Treg cell stability in cancer.
- Published
- 2019