. Author manuscript; available in PMC: 2018 Aug 1.

Published in final edited form as: Nat Rev Immunol. 2017 Oct 9;18(2):91–104. doi: 10.1038/nri.2017.112

Table 1.

Summary of other major immune checkpoint pathways

Checkpoint Receptor	Cell type affected	Ligand	Notes	Ref.
T cell immunoglobulin and mucin-domain containing-3 (TIM3; HAVCR2 in humans)	Th1-T cells	Galectin-9 on APC	Galectin-9 induces intracellular calcium flux, aggregation and death of Th1 cells in vitro. Co-expression of TIM3 and PD-1 identifies CD8⁺ T cell in mice with an exhaustion phenotype. Targeting TIM3 and PD-1 pathways can reverse T cell exhaustion and restore anti-tumor immunity.	^140–142.
Lymphocyte activation gene 3 (LAG3; CD223)	iTreg, nTreg	MHC Class II on APC	LAG3 enhances the function of regulatory T cells. LAG3 and PD-1 are commonly co-expressed on anergic or exhausted T cells and combined blockade can cure most mice of established tumours that were largely resistant to single antibody treatment.	^143,144.
T cell immunoreceptor with Ig and ITIM domains (TIGIT)	T cells, NK	CD155 on DCs	CD96 & TIGIT exert immunosuppressive effects by competing with CD226 for CD155. TIGIT-Fc fusion protein inhibits T cell activation by generating regulatory DCs. Blocking CD96 or TIGIT with mAbs improve tumor control in mice, in particular when used in combination with PD-1/PD-L1 blockade.	^145–148.
CD96	T cells, NK	CD155 on DCs		^145–148.
B and T lymphocyte attenuator (BTLA; CD272)	Naïve T and B cells and is further upregulated on activation.	Herpesvirus entry mediator (HVEM) expressed by most hematopoietic, endothelial & epithelial cells	Ligation of LIGHT by HVEM can be co-stimulatory, while BTLA-HVEM binding is considered co-inhibitory. BTLA has been linked to T cell dysfunction during cancer and dual blockade of BTLA and PD-1 clearly enhances anti-tumour immunity	^149–152.
Tumor necrosis factor superfamily member 14 (TNFSF14; LIGHT)	Innate and adaptive immune cells including T cells			^149–152.
Glucocorticoid-induced TNFR-related protein (GITR)	Regulatory T cells at high levels, resting conventional T cells at low levels but increases upon activation	GITR-ligand on APC	GITR plays a key role in dominant immunological self-tolerance maintained by CD25⁺CD4⁺ regulatory T cells. The ligand for GITR is mainly expressed on APC and antibodies to GITR have been shown to promote an anti-tumor response through loss of Treg lineage stability.	^153–156.
V-domain immunoglobulin (Ig)-containing suppressor of T cell activation (VISTA)	Hematopoietic cells	unknown	Preclinical studies with VISTA blockade show promising improvement in anti-tumor T cell responses and improved survival.	^157,158.