IL-33-ILC2 axis promotes anti-tumor CD8⁺ T cell responses via OX40 signaling

Group 2 innate lymphoid cells (ILC2s) are resident cells and participate in innate and adaptive immunity. In the tumor microenvironment (TME), ILC2s contribute to both tumorigenesis and inhibition of tumor growth, but the true role of ILC2s in TME construction remains unclear. We show that IL-33 treatment induces an anti-tumor effect in vivo in a mouse model of melanoma in which ILC2s and CD8⁺ T cells infiltrate into tumor tissue. This anti-tumor effect is dependent on CD8⁺ T cells, however, IL-33 does not act directly on CD8⁺ T cells because the cells lack ST2, the receptor for IL-33. ILC2s and CD8⁺ T cells in tumors of IL-33-treated mice express OX40 ligand (OX40L) and OX40, respectively, and in vivo blockade of OX40L-OX40 interaction canceled the anti-tumor effect of IL-33. Co-culture of CD8⁺ T cells expressing OX40 with IL-33-stimulated ILC2 expressing OX40L promoted cell activation and proliferation of CD8⁺ T cells, which was significantly suppressed by administration of anti-OX40L blocking antibody. Thus, the IL-33-ILC2 axis promotes CD8⁺ T cell responses via OX40/OX40L interaction and exerts an anti-tumor effect.