Panayotis Verginis and colleagues recently published a study in Nature Immunology

Despite impressive clinical success, cancer immunotherapy remains ineffective in large proportion of patients due to tumoral resistance, which is dependent on the immunosuppressive nature of tumor microenvironment (TME). Regulatory T cells (Tregs) are the most abundant immune cells in the TME and their presence has been correlated with tumor progression, invasiveness as well as metastasis. Importantly, mounting evidence suggests that intratumoral accummulation of Tregs is a fundamental impediment to the success of cancer immunotherapy. Although major efforts have been placed to delineate the mechanisms that tumors promote Treg induction, function and expansion, the molecular and functional features of Tregs in cancer patients remain largely unknown. In this report, we describe a cell-intrinsic role of the alarmin IL-33 in Treg cell functional stability during tumor development. Ablation of IL-33 expression by Foxp3+ Treg cells resulted in tumor regression while IL-33-deficient Treg cells exhibited impaired suppressive properties, promoted tumor eradication, accompanied by a robust anti-tumor immunity. Notably, in the absence of IL-33 Treg cells present a “fragile” phenotype characterized by the up-regulation of IFN- expression. Finally, genetic ablation of Il33 potentiated the therapeutic efficacy of checkpoint inhibitor immunotherapy. In conclusion, this work reveals a novel intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion and it also opens new avenues for design of antitumor therapies based on the induction of Treg cell fragility.

An intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion
Hatzioannou A, Banos A, Sakelaropoulos T, Fedonidis C, Vidali MS, Köhne M, Händler K, Boon L, Henriques A, Koliaraki V, Georgiadis P, Zoidakis J, Termentzi A, Beyer M, Chavakis T, Boumpas D, Tsirigos A, Verginis P.
Nat Immunol. 2020 Jan;21(1):75-85. doi: 10.1038/s41590-019-0555-2. Epub 2019 Dec 16.
PMID: 31844326

Pubmed