Currently, rapid development of immunotherapy is revolutionizing the area of tumor therapy. However, most patients couldn’t benefit from available immunotherapy strategies due to limited efficacy and safety, especially under the setting of solid tumors. 

Natural killer cells (NK cells) are cytotoxic innate immune cells, which play an important role in immune surveillance against tumors. However, the underlying mechanisms are still poorly understood. 

Dr. TIAN Zhigang's group from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences reported that tumor necrosis factor-α (TNF-α)-induced protein-8 like-2 (TIPE2) suppressed NK cell maturation and anti-tumor immunity. This finding indicates that TIPE2 is a checkpoint molecule of NK cells, and targeting TIPE2 may benefit NK-based tumor immunotherapy. 

Their study was published in Science Advances on Sept. 15.

Previous studies of Dr. TIAN's group have already revealed the roles of checkpoint receptors T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and A3AR on NK cell functions in tumor surveillance, tissue injury and regeneration.

Based on these studies, they kept on searching for checkpoint molecules during NK cell maturation, the process during which NK cells acquired optimal functions.

The researchers conducted single cell transcriptomic analysis of both human and mouse peripheral NK cells at the steady state. They found that either human or mouse NK cells were comprised of several sub-populations correlating with the NK cell maturation process from "immature" NK cells to "mature" NK cells. Importantly, TIPE2, a molecule previously reported to mediate immune tolerance, increased its expression along with the NK cell maturation process.

The researchers also investigated the role of this molecule in NK cell biology. They found that in NK-specific TIPE2 deficient mice, the levels of mature NK cells increased, and NK cells displayed enhanced effector functions, indicating that TIPE2 suppressed NK cell functional maturation. 

Furthermore, NK-specific TIPE2 deficient mice showed better control of tumor growth in vivo, accompanied by increased tumor infiltration of NK cells, and by enhanced effector functions of tumor-infiltrating NK cells. 

These results suggested a promising approach of targeting TIPE2 for NK cell-based immunotherapies.