Antigen Cross-Presentation by Type-2 Innate Lymphoid Cells Facilitates the Activation of Antitumor CD8⁺ T Cells

Type-2 innate lymphoid cells (ILC2) exhibit dual functions in cancer, both promoting and inhibiting tumor growth by regulating antitumor immune responses. Elucidation of the precise mechanisms by which ILCs regulate adaptive immune responses could support the development of improved immunotherapeutic approaches. In this study, we revealed that ILC2s possess the capacity to internalize, process, and present exogenous tumor antigen on MHC-I molecules, along with costimulatory molecules, to CD8⁺ T cells, thereby inducing their differentiation into CTLs. Transferring ILC2s into tumor-bearing mice resulted in CD8⁺ T-cell–dependent inhibition of tumor growth. Moreover, coculturing CD8⁺ T cells with ILC2s upregulated the expression of cytotoxic molecules, leading to efficient killing of cancer cells in vitro as well as in vivo upon transfer into tumor-bearing mice. Mechanistically, ILC2s employed clathrin-dependent endocytosis to internalize exogenous antigens and process/present them to CD8⁺ T cells as effectively as conventional antigen-presenting cells. Based on this study, ILC2s emerge as proficient antigen-presenting cells capable of stimulating the tumor-killing activity of CD8⁺ T cells, thus offering promising antitumor immunotherapeutic strategies. Significance: Type-2 innate lymphoid cells process and present tumor antigens to CD8⁺ T cells to increase cytotoxic activity against cancer cells, highlighting the potential to harness this intercellular interaction to improve cancer treatment.