Table 4.

Immunosuppressive factors used by cancer cells to escape immune system control.

Immunosuppressive Factor	Action
Decreased production of arginine	Arginine-deprived T cells exhibit decreased proliferation and survival [57,60] L-arginine is a precursor of nitric oxide synthesis, which inhibits T cell expansion and function [61,62]
High level of adenosine	Inhibition of NK cells infiltration and function [63] Impairment of macrophage activation [63] Promotion of the Treg maturation [63] Impediment of Teff initiation, proliferation, and ability to release cytokines [63]
High level of indoleamine 2,3-dioxygenase (IDO)	Inhibition of the immune response by reduction in the tryptophan level, necessary for T cell proliferation [66] Promotion of Treg migration into the tumor area [66] IDO-mediated local tryptophan deficiency activates the process of autophagy and leads to T cell anergy [68,69]
High level of kinurenine	Inhibition of NK cell cytolytic activity [70] Promotion of Treg differentiation, reduction in APC immunogenicity, and upregulation of PD-1 expression on Teff cells [71,72]
Acidification within the tumor niche	Stimulation of TAMs polarization towards M2 type [77] Reduction in CD8+ T cells cytolytic activity [78] Increased secretion of IL-1β by monocytes and TAMs [78]
Exosomes	Source of ligands, such as PD-L1, which inhibit the anti-tumor response through interaction with receptors present on T cells [79] Transport of soluble factors, such as Fas and TRAIL, which induce Teff cell apoptosis [80] Exosomes with high IL-6 content can inhibit monocyte differentiation into DCs [81]

Abbreviations: NK—natural killer cell, Tregs—regulatory T cells, Teffs—effector T cells, NKG2D—natural killer group 2D receptor, IL-1β—interleukin 1β, PD-1—programmed cell death protein 1, TAMs—tumor-associated macrophages, PD-L1—programmed death ligand 1, CTLA-4— cytotoxic T-lymphocyte associated protein 4, DCs—dendritic cells, TRAIL—TNF-related apoptosis inducing ligand, IL-6 - interleukin 6.