An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion


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.

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Fig. 1: IL-33 deficiency promotes anti-tumor immunity and inhibits tumor growth.
Fig. 2: Host-derived IL-33 role in tumor regression.
Fig. 3: Impaired suppressive function of IL-33-deficient Treg cells in vivo.
Fig. 4: IL-33-deficient Treg cells acquire a fragile phenotype.
Fig. 5: Role of IFN-γ in the impaired suppressive function of Il33−/− Treg cells.
Fig. 6: Increased NF-κB activation and T-bet expression promote IFN-γ production in Il33−/− Foxp3+ Treg cells.
Fig. 7: IL-33 deficiency potentiated immunotherapy efficacy.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. The RNAseq and ATACseq data have been deposited in the Gene Expression Omnibus with the accession code GSE138874.


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We thank T. Alissafi for fruitful conversations and critical reading of the manuscript, R.M. Barouni for technical assistance, P. Alexakos for technical assistance on animal handling and maintenance and A. Apostolidou for technical assistance on flow cytometry and cell sorting. We also thank M. Makridakis and G. Kontostathi for PRM analysis. This work was supported by grants from the GGSRT (no. Aristeia II 3468 to P.V.). M.B. was funded by the German Research Foundation (grant no. BE 4427/3-1) and is a member of the excellence cluster ImmunoSensation. T.C. was supported by the ERC (grant no. DEMETINL-683145) and the German Research Foundation (grant no. SFB 1181, CO7). D.B. was supported by the ERC under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 742390). A.Hatzioannou is supported by IKY Fellowships of Excellence for Postgraduate Studies in Greece, Siemens Program and ‘Stratigos’ grant of the Hellenic Society of Melanoma Study. A.B. is financed by Greece and the European Union (European Social Fund) through the Operational Program ‘Human Resources Development, Education and Lifelong Learning’ in the context of the project ‘Reinforcement of Postdoctoral Researchers’ (no. MIS-5001552), implemented by the State Scholarships Foundation. D.B. and P.V. were supported by the European Union’s Horizon 2020 research and innovation program (grant agreement no. 733100).

Author information

A.Hatzioannou and A.B. designed and performed experiments, analyzed the data, generated the figures and wrote the manuscript. C.F., M.-S.V., M.K., K.H. and A.Henriques performed experiments and analyzed the data. L.B. generated and provided critical reagents. T.S. and A.Tsirigos assisted with mRNA-seq and ATAC-seq data analysis and interpretation. T.S. generated the figures. J.Z. and A.Termentzi performed and analyzed the targeted proteomics experiments. V.K., P.G. and M.B. contributed to the data analysis and interpretation. T.C. and D.B. interpreted the data. P.V. designed and supervised the study, performed the data analysis and wrote the manuscript.

Correspondence to Panayotis Verginis.

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Hatzioannou, A., Banos, A., Sakelaropoulos, T. et al. An intrinsic role of IL-33 in Treg cell–mediated tumor immunoevasion. Nat Immunol 21, 75–85 (2020).

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