Table 1.
Mechanisms of immunosuppression in gliomas
| Type | Mechanism | Examples | References |
|---|---|---|---|
| Tumor-cell intrinsic | Glioma-mutations and effect on tumor microenvironment | IDH1-R132H mutation: Downregulates effector molecules like IFNγ, Granzyme-b, CXCL9, CXCL10 thereby reduces total CD8+ T-cell numbers in the tumors | (58,60) |
| NF1 loss: Increases M2-like macrophages/microglia in tumors | (20) | ||
| N-Myc amplification: Decreases IFNγ, CXCL10 resulting in poor infiltration of T-cells to tumors | (75) | ||
| Mesenchymal subtype of tumors: Enhances M2 macrophages/microglia, reduces responses to radiation, increases PD-L1 on tumors | (20) | ||
| Absence tumor hypermutation: Decreases T-cells in tumors | (15,16) | ||
| Glioma-associated downregulation of HLA and antigen presentation | Loss of Heterozygosity (LOH) in HLA: Associates with shorter survival and decrease in intra-tumoral CD8+ T-cells | (76) | |
| Tapasin: Closely associates with HLA-loss, levels correlate with survival | (77) | ||
| Glioma expression of immune-checkpoint receptors | PD-L1: Higher expression correlates with worst prognosis. Suppresses CTL proliferation and function | (13) | |
| CTLA4: Modulates T-cell activation to an immune-suppressive state | (78) | ||
| Glioma-specific receptors suppressing T-cell proliferation/function | GLUT1: Increases expression on glioma cells, enhances glucose intake, reduces T-cell proliferation by competition in glucose uptake | (78,79) | |
| Galectin-1: Inhibits T-cell proliferation and effector responses. Increases MDSC and immune-suppressive macrophages in tumor microenvironment | (55) | ||
| STAT3: GBM Cancer initiating cells inhibits CTL proliferation and function, induces Tregs, triggers T-cell apoptosis through STAT3 | (41) | ||
| Glioma-induced immune-modulatory molecules | TGF-b: Polarizes T-cells, macrophages, microglia to immune-suppressive states. Inhibits effector responses in T-cells, downregulates MHC-II on glioma cells and myeloid cells, promotes Treg activity. | (80) | |
| VEGF: Causes downregulation of ICAM-1 and VCAM-1, inhibits T-cell transmigration through GBM vessels | (52) | ||
| Glioma-induced T cell apoptosis | CD70: Mediates T-cell apoptosis upon interaction with CD27 | (81) | |
| Gangliosides: Mediates T-cell apoptosis | (81) | ||
| Tumor-cell extrinsic | Suppression in CTL responses by immune-suppressive TAMs, Microglia and MDSC | IL-6: Suppresses effector cell responses. Activates STAT3 to further inhibit T-cell proliferation and function. Increases infiltration of suppressive TAMs and Microglia through IL-6-CCL2-CCR2 loop | (41,82) |
| IL-10: Inhibits IFNγ, TNFα and T-cell function, promotes Tregs, downregulates CD80, CD86, MHC-II in myeloid cells causing CD8+ T-cell anergy | (40) | ||
| FasL: Induces T-cell apoptosis | (83) | ||
| IL-4Ra: Promotes MDSC in glioma microenvironment, produces immune-suppressive arginase, inhibits T-cell proliferation and function | (42) | ||
| CCL2: Induces Treg, increases infiltration of TAMs, microglia and MDSC that produce CTL inhibitory factors | (38) | ||
| PGE2: Induces regulatory DC, leads to differentiation and accumulation of suppressive MDSC, reduces Th1 cytokine secretion | (45) | ||
| Regulatory T cell mediated suppression of CTLs | GITR: Induces Treg expansion, inhibits CTL function, leads to secretion of IL-10 and suppresses APC function | (45) | |
| IDO1: Increase in IDO levels in glioma associates with poor prognosis. Inhibits T-cell proliferation and function, induces Treg recruitment to tumors, reduces CTL infiltration to tumors | (84) | ||
| Hypoxia | Causes abnormal glioma vasculature, increases VEGF secretion, downregulates ICAM and VCAM molecules thereby inhibiting CD8+ T- cell infiltration to tumors, activates Tregs via STAT3, increases immune-suppressive mechanisms by promoting M2-type myeloid cells in tumors | (85) | |
| Immune-privilege of CNS | Differential homing patterns in CNS versus periphery | T-cell homing to CNS compared to periphery is a two-step process. First step involves crossing the post-capillary venular endothelium and second step involves crossing the glia limitans | (86) |
| Lack of resident T-cells or professional APCs in brain parenchyma. Decrease in MHC-II expression on APCs inhibits antigen presentation in parenchyma of CNS | (86) | ||
| Afferent perivascular drainage pathway for ISF from CNS to regional cervical lymph nodes prevents cellular trafficking. Immune cells traffic through CSF’s lymphatic drainage | (86,87) |