IL-33 Amplifies Regulatory T Cell Reprogramming

Abstract

CD4+ Foxp3+ T regulatory (Treg) cells are essential to maintain immune homeostasis and immunological self-tolerance. Their immunosuppressive functions are beneficial in preventing autoimmune diseases but detrimental in supporting tumor growth. Tumor infiltrating Treg cells suppress anti-tumor immune responses and promote tumor immune escape. To unleash anti-tumor responses and improve prognosis in cancer patients, multiple therapeutic strategies have been developed to selectively deplete tumor infiltrating Treg cells. In order to more effectively regulate T cell responses, activated Treg cells can express the transcription factors that define the Th1, Th2 and Th17 effector cell lineages and adopt some of their functional attributes, a phenomenon described as Treg plasticity. However, Th1-, Th2-, or Th17-polarized Treg cells in most cases do not express the respective effector cytokines. Our laboratory has previously shown that tumor-infiltrating Treg cells not only adopt Th1 features, but can also secrete IFN at a low rate, that the rate of IFN-secretion can be amplified by targeting the CARMA1-BCL10-MALT1 (CBM) signalosome complex in Treg cells, and that Treg cell-derived IFN inflames the tumor microenvironment (TME) selectively to render immune checkpoint therapy (ICT)-resistant tumors sensitive to PD-1 pathway-targeted ICT without leading to autoimmune responses outside of tumor. This has led to the novel concept to harness Treg cells therapeutically to inflame the TME instead of depleting them. To investigate which TME factors promoted IFN production by Treg cells selectively in the TME, we screened for TME cytokines and observed that the IL-1 family cytokines IL-18 and IL-33 synergized with IL-12 to reprogram Treg cells to secrete IFN. It has been shown that IL-18 enhances IFN production by Th1 cells, while IL-33 enhances IL-5 and IL-13 production by Th2 cells. Therefore, we first examined the effects of IL-33 on Th1-, Th2-, and Th17-polarized Treg cells. We found that IL-33 enhanced not only T-bet and IFN expression in Th1-like Treg cells, but also GATA3 expression in Th2-like Treg cells, while we did not observe an effect on RORt and IL-17A expression in Th17-like Treg cells. This result indicates that IL-33 has pleiotropic roles in promoting Treg cell polarization. In many patients, cancer cells express IL-33, and we hypothesized that cancer cell-derived IL-33 could amplify Treg cell-secretion of IFN, supporting sensitivity to ICT in these patients. In contrast to this hypothesis, we observed reduced tumor growth in Treg cell-specific conditional ST2 (IL-33-receptor) knockout mice implanted with IL-33-expressing tumors, indicating that the immunosuppressive function of IL-33/ST2 signaling in tumor infiltrating Treg cells outweighs any potential pro-inflammatory effects.