Natural killer cells (NK cells) play an important role in immune surveillance against tumors

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Currently, immunotherapy is revolutionizing tumor therapy.

However, most patients can’t benefit from available immunotherapy strategies due to limited efficacy and safety, especially those with solid tumors.

Natural killer cells (NK cells) are cytotoxic innate immune cells that 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 searched 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 human and mouse NK cells comprised 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.


Natural killer (NK) cells are lymphocytes that can mediate lysis of certain tumor cells and virus-infected cells without previous activation. They can also regulate specific humoral and cell-mediated immunity. NK cells preferentially express several calcium-dependent (C-type) lectins, which have been implicated in the regulation of NK cell function. The NKG2 gene family is located within the NK complex, a region that contains several C-type lectin genes preferentially expressed in NK cells. T

his gene encodes a member of the NKG2 family. The encoded transmembrane protein is characterized by a type II membrane orientation (has an extracellular C terminus) and the presence of a C-type lectin domain. It binds to a diverse family of ligands that include MHC class I chain-related A and B proteins and UL-16 binding proteins, where ligand-receptor interactions can result in the activation of NK and T cells.

The surface expression of these ligands is important for the recognition of stressed cells by the immune system, and thus this protein and its ligands are therapeutic targets for the treatment of immune diseases and cancers. Read-through transcription exists between this gene and the upstream KLRC4 (killer cell lectin-like receptor subfamily C, member 4) family member in the same cluster. [provided by RefSeq, Dec 2010]

reference link: https://www.ncbi.nlm.nih.gov/gene/22914


More information: Jiacheng Bi et al, TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity, Science Advances (2021). DOI: 10.1126/sciadv.abi6515

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