Soluble immune checkpoints in cancer: production, function and biological significance

Table 1 Basic information about the soluble receptors and ligands

Soluble receptors/ligands	Structure	Cell source	Production	Ligands/receptors	Main functions	references
sPD-1	Monomer	PBMCs (peripheral blood mononuclear cells)	mRNA expression	PD-L1/2	1. Block PD-L/PD-1 interactions 2. Activate CD8⁺ T cells	[4, 19, 20, 23, 24]
sPD-L1	Unknown	Mature DCs	Possible cleavage of membrane-bound proteins	PD-1	1. Combine with PD-1 2. Inhibit T-cell responses	[31, 32, 44]
sPD-L2	Unknown	Activated leukocytes	mRNA expression	PD-1	Unknown	[45]
sCTLA-4	Monomer	Monocytes/immature DCs/Treg cells	mRNA expression	CD80/CD86	Inhibit T-cell responses	[46, 47, 51, 52]
sCD80 (sB7–1)	Homodimer	Unstimulated monocytes/B cells	mRNA expression	CTLA-4 /CD28	Inhibit PD-1/PD-L1 pathway	[53, 54, 56, 59, 60]
sCD86 (sB7–2)	Monomer	Resting monocytes/DCs	Cleavage of membrane-bound proteins/mRNA expression	CTLA-4	Inhibit T-cell responses	[65, 69]
sB7-H3	Unknown	Monocytes/ DCs/activated T cells	Cleavage of membrane-bound proteins/mRNA expression	B7-H3R	Promote IL-8 and VEGF expression	[70, 71, 77]
sCD137 (s4-1BB)	Unknown	Activated PBMCs	Cleavage of membrane-bound proteins/mRNA expression	CD137L	Inhibit CD137/CD137L pathway	[78, 79, 82]

For example, sPD-1 has been reported to be a monomer, and it can be produced by PBMCs through mRNA expression. Moreover, sPD-1 can combine with PD-L1 and PD-L2, thus blocking PD-L/PD-1 interactions and somehow activating CD8+ T cells. Some soluble receptors can be produced by the cleavage of membrane-bound proteins or by both the cleavage of membrane-bound proteins and mRNA expression