ILC2s directly activate anti-tumor cytotoxic CD8+ T lymphocytes by internalizing, processing, and presenting exogenous antigens
Type-2 innate-lymphoid cells (ILC2s) associate with both tumor promotion and inhibition. We found that ILC2s may induce anti-tumor immunity by a hitherto-unrealized mechanism: they may internalize, process, and present exogenous tumor antigen on major-histocompatibility-complex class-I (MHCI) molecules with costimulatory molecules to CD8+ T cells. This converts the T cells into cytotoxic-T-lymphocytes (CTLs). Specifically, transferring ILC2s into tumor-bearing mice inhibited tumor growth in a CD8+ T cell-dependent manner. Moreover, co-culturing human or murine CD8+ T cells with ILC2s upregulated T-cell expression of cytotoxic molecules. The resulting CTLs efficiently killed tumor cells in vitro and upon transfer into tumor-bearing mice. ILC2s were found to internalize exogenous antigens via clathrin-dependent endocytosis and to process/present them as efficiently as professional antigen-presenting cells for CD8+ T cells (type-1 conventional dendritic cells). Thus, ILC2s can present antigen to CD8+ T cells and induce their tumor-killing activity. This novel finding has promising implications for anti-tumor strategies. Overall design: Isolated CD8+ T cells and ILC2s were co-cultured with 5:1 ratio for 3 days. Bulk RNA sequencing was performed on co-cultured CD8+ T cells and ILC2s, with individually cultured CD8+ T cells or ILC2s serving as control groups. A total of 1x106 cells from each group were isolated using BD FACSAria™ III through flow cytometry. Each group included 2 replicates.