. CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China . Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China . Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, China . Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning 530021, China . Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Key Laboratory of Colleges and Universities, Nanning 530021, China . Collaborative Innovation Center of Regenerative Medicine and Medical BioResource Development and Application, Guangxi Medical University, Nanning 530021, China . The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China . Institute of Immunology, University of Science and Technology of China, Hefei 230027, China . Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Beijing 100864, China
Natural killer (NK) cells are key innate immune lymphocytes, which play important roles against tumors. However, tumor-infiltrating NK cells are always hypofunctional/exhaustive. On the one hand, this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands, which usually vary in different tumor types and stages during tumor development. On the other hand, the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types, representing common mechanisms limiting the potential of NK cell therapy. In this review, representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed, and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.
Fig.1 Intracellular checkpoint molecules from different aspects of NK cell biology. Representative molecules are as follows: FBP-1 related to metabolism, EZH2 related to epigenetics, CIS and TIPE2 as negative IL-15 signaling regulators, HIF-1α associated with hypoxia, Cbl-b associated with protein ubiquitination, and BIM related to apoptosis. These intracellular checkpoints contributed to NK cell exhaustion by different aspects.
Fig.2 Several known intracellular checkpoints of NK cells described in this article (e.g., BIM, FBP1, Cbl-b, EZH2, CIS, TIPE2, and HIF-1α) mediate the depletion state of NK cells (upper part of the figure), which is manifested by an overall decline in the activation function, glycolysis, cytotoxicity, survival, and proliferation of NK cells. The level of apoptosis increased, and the amount of IFN-γ produced decreased sharply and finally lost the antitumor ability. By knocking out one or more intracellular checkpoints in NK cells by CRISPR Cas9 technology (bottom half of the figure), the depletion state of NK cells can be reversed, and the cytotoxic effect of NK cells to produce high levels of IFN-γ can be restored. Consequently, NK cells can regain antitumor ability.
Fig.3 Tumor-infiltrating NK cells are immunosuppressed by various factors and are often in a state of immune exhaustion. Various cells in the tumor microenvironment (such as Treg, MDSC, and tumor cells) secrete the immunosuppressive factor TGF-β. TGF-β transmits inhibitory signals downward by acting on the corresponding receptors on the surface of NK cells. Simultaneously, the level of the intracellular checkpoint molecule FBP1 increases. By blocking this process with inhibitors of FBP1, the depletion state of NK cells can be reversed, and the secretion of cytotoxic cytokines (such as IFN-γ, perforin, and granzymes) by NK cells can be increased to promote the antitumor effect of NK cells.
Regulatory effects
Molecules
References
Cytotoxicity (?)
CIS, TIPE2, Cbl-b, EZH2
[28,30,64,158–162]
Survival (?)
CIS, EZH2
[30,158,159,161]
Proliferation (?)
CIS, EZH2,TIPE2
[30,86,158,161]
Metabolism (?)
FBP1, HIF-1α
[29,155]
Apoptosis (+)
BIM
[31,57]
Mechanisms of action
Molecules
References
Signaling transduction
CIS, TIPE2
[30,159,161,162]
Transcription
HIF-1α
[155]
Epigenetics
EZH2
[158]
Post-translational modifications
Cbl-b
[64]
Pro-apoptotic protein
BIM
[31,57]
Tab.1 Intracellular checkpoint molecules involved in NK cells
Fig.4 NK cells of different origin are used in the immunotherapy of tumors. At present, three known methods can be used to obtain modified NK cells: (1) induced pluripotent stem cell (iPSC)-derived NK cells (iPSC NK) are genetically edited at the iPSC stage and are monoclonal, and such cells are differentiated into NK cells; (2) peripheral blood-derived NK cells (PBNK) are directly edited on NK cells; (3) the human NK cell line NK92 was edited and monoclonal on NK92.
Fig.5 Timeline of the intracellular checkpoints of NK cells. In recent years, with the gradual deepening of the research on NK cells, an increasing number of new intracellular checkpoints have been discovered. Intracellular checkpoints inhibit the growth, survival, proliferation, differentiation, cytotoxicity, and antitumor effects of NK cells, leading to the exhaustion of tumor-infiltrating NK cells.
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