Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8+ T Cells

Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8(+) T-cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T-bet/Eomes-IFN-gamma axis in NK cells is essential for CD8(+) T cell-dependent tumor control, whereas T-bet-dependent NK cell effector functions are required for an optimal response to anti-PD-L1 immunotherapy. Importantly, NK cell-expressed TIPE2 (tumor necrosis factor-alpha-induced protein-8 like-2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK-intrinsic antitumor activity but also indirectly improves the antitumor CD8(+) T cell response by promoting T-bet/Eomes-dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell-based immunotherapy.

Automated summary

Natural killer (NK) cells play dual roles in tumor surveillance and CD8(+) T-cell response. The T-bet/Eomes-IFN-gamma axis in NK cells is essential for CD8(+) T cell-dependent tumor control, and T-bet-dependent NK cell effector functions are required for an optimal response to anti-PD-L1 immunotherapy. NK cell-expressed TIPE2 represents a checkpoint molecule for NK cell helper function, and its targeting might boost both the antitumor T cell response and T cell-based immunotherapy.