Table 1.

Mechanisms of immunosuppression in the tumor microenvironment

Mediator	Mechanism of immunosuppression	References
Cell surface proteins
Programmed death-ligand 1	Induce T-cell tolerance/anergy after ligation with programmed cell death protein 1 on T cells	37
CTLA-4	Inhibit activation of naïve T cells	37
	Enhance regulatory T cell function	74
↓Major histocompatibility complex I	Avoid detection by effector CD8 T cells	75
↓FAS	Avoid FAS ligand–mediated cell killing
↓TRAIL	Avoid TRAIL-mediated cell killing
CD39/CD73	Convert extracellular immunostimulatory adenosine triphosphate to immunosuppressive adenosine	76
Secreted cytokines
Transforming growth factor beta	Inhibit T cell priming and infiltration	77
	Suppress effector cell cytotoxicity	47
Vascular endothelial growth factor	Inhibit dendritic cell maturation	78
	Enhance programmed cell death protein 1/programmed death-ligand 1/2 expression	79
	Enhance interleukin-10 secretion
Interleukin-10	Inhibit major histocompatibility complex II expression on antigen presenting cells	80
	Suppress M1 cytokine secretion	81
	Suppress iNOS (inducible Nitric Oxide Synthase)	82
	Induce T cell anergy	83
Metabolic pathways
Indoleamine-2,3 dioxygenase	Convert tryptophan to kynurenine	55
	Inhibit T cell proliferation	84
Adenosine	Inhibit T cell proliferation and activation	85, 86
Hypoxia	Inhibit effector T cell function	87
	Promote prostaglandin E2 synthesis	88
Lactate	Inhibit effector T cell function	89
Arginase	Degrades L-arginine needed for cytotoxic iNOS production	90
Prostaglandin E2	Inhibit effector T cell function	91, 92
	Suppress M1 cytokine secretion	93
	Recruit myeloid-derived suppressor cells	94

Abbreviations: CD = cluster of differentiation; TRAIL = tumor necrosis factor-related apoptosis-inducing ligand.