. 2020 Oct 29;5:250. doi: 10.1038/s41392-020-00348-8

Table 1.

Preclinical experiments in promising cancer target of immune checkpoints

Immune checkpoint receptors	Treatment	Ligands	Signaling motif	Receptor adapter	Key results
Stimulating family
NKG2D	NKG2D ligand α3 domain-specific antibodies, anti-NKG2A protein expression blockers (PEBLs)	MICA, MICB, and the ULBP family	YINM	DAP-10, DAP-12	The α3 domain-specific MICA/B antibody stimulated NK cells to produce IFN-γ and TNF-α²⁰⁹
KIR2DS/KIR3DS	Transfection of KIR2DS and DAP-12	classical HLA class I	ITAM	DAP-12	DAP-12 expression enhanced surface expression on NK cells and stability of KIR2DS²²⁵
Inhibitory family
KIRs	Transfection of KIR-Fc GL183, EB6, DF200 and Pan2D (NKVSF1)	classical HLA class I	ITIM		KIR and HLA class I ligand interactions modulate NK cell immunity and antitumor activity^25,22,228
TIGIT	13G6, SHIP-1 silencing, Y225A mutation	CD155, CD112, CD113	ITIM/ITT		Blockade of TIGIT signaling prevents NK cell exhaustion and enhances potent antitumor immunity^92,97,105
CD96	3.3 mAb, 6A6 and 8B10	CD155	ITIM/YXXM		Anti-CD96 mAbs promote NK cell anti-metastatic activity in CD115-dependent and CD115-independent manner¹²⁰
LAG-3	mAbs blocking FGL1/LAG-3 binding	MHC class II molecules, Fibrinogen-like Protein 1	KIEELE		mAbs blocking FGL1/LAG-3 binding stimulates tumor immunity¹⁸¹
NKG2A	anti-NKG2A PEBLs	HLA-E	ITIM		Anti-NKG2A PEBL transduction inhibited NKG2A expression without affecting NK cell proliferation, and generated more potent cytotoxicity than an anti-NKG2A antibody. The NKG2A^null NK cells increased NK cell killing of HLA-E–expressing tumors in vivo⁴³
TIM-3	mAbs blocking TIM3-Fc binding to Gal-9, phosphatidylserine, Ceacam-1	Gal-9, phosphatidylserine, HMGB1, Ceacam-1	Tyrosine		Anti-Tim-3 antibodies inhibited Tim-3 signaling to improve the proliferation and cytotoxic activity of CD8⁺ TILs and reduce tumor-promoting cytokines production^146,147