Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

Table 1

Mechanisms of immune privilege.

General peripheral tolerance	Ref
T cell negative selection in thymus	[6]
Natural (thymic) Tregs	[7, 8]
Acquired (adaptive) Tregs	[9, 10]
Local immunosuppression (IDO, TGF-β, IL10, CTLA-4)	[11–27]
CNS-specific privilege	Ref
Reduced lymphatic transport to draining lymph nodes	[28–33]
Lack of resident immunogenic APCs (dendritic cells)	[28, 29, 34–37]
Specialized endothelium excludes naïve T cells	[28, 29, 34, 35, 38]
Local immunosuppression by astrocytes and microglia	[28, 35, 38–41]
Tumor-induced immunosuppression (CNS and non-CNS)	Ref
Local activation of natural Tregs	[7, 42–44]
Tumor-specific (adaptive) Tregs	[42, 44–48]
Local intratumoral immunosuppression
IDO	[16, 45, 47–53]
Arginase	[42, 54, 55]
TGF-β	[56–59]
IL10	[60, 61]
CTLA-4	[11, 62–65]
PD-L1	[11, 46, 62, 66]
Myeloid-derived suppressor cells	[67–70]
Tolerogenic APCs	[42, 44, 45, 47, 48, 61, 71–73]
Tolerogenic draining lymph nodes	[45, 47, 48, 73]
Quiescent vascular endothelium	[74–79]

Tregs: regulatory T cells; IDO: indoleamine 2,3-dioxygenase; TGF-β: transforming growth factor-beta; IL10: interleukin-10; CTLA-4: cytotoxic T lymphocyte antigen-4; PD-L1: programmed death ligand-1; APCs: antigen-presenting cells.