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

Abstract Type-2 innate lymphoid cells (ILC2s) exhibit dual functions in cancer, both promoting and inhibiting tumor growth by regulating anti-tumor immune responses. Elucidation of the precise mechanisms by which ILCs regulate adaptive immune responses could support development of improved immunotherapeutic approaches. Here, we revealed that ILC2s possess the capacity to internalize, process, and present exogenous tumor antigen on major histocompatibility complex class I (MHC I) molecules, along with costimulatory molecules, to CD8+ T cells, thereby inducing their differentiation into cytotoxic T lymphocytes (CTLs). Transferring ILC2s into tumor-bearing mice resulted in CD8+ T cell-dependent inhibition of tumor growth. Moreover, co-culturing 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 anti-tumor immunotherapeutic strategies.