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Page 695 Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82

T cell exhaustion
T cell exhaustion is exceptionally severe in glioblastoma , resulting in poor therapeutic efficacy of
[110]
immunotherapy. Most immunotherapies focus on eliciting an anti-tumor T cell response that requires a
collaboration of at least CD4 T Helper cells and CD8 cytotoxic T cells (CTLs). CD4 T Helpers can modulate
antigen-specific immune response through their high plasticity and cytokine production, while CD8 CTLs
exert cancer cell killing through direct cell-cell interaction and targeted release of effector molecules
(perforin and granzymes) . T cell exhaustion is mainly induced by persistent antigen exposure, and it is
[111]
commonly seen in chronic infections and cancers. It is generally characterized by elevated expression of
various immune checkpoints (PD-1, CTLA-4, LAG-3, and TIM-3). Remarkably, T cell exhaustion was also
found to correlate with hypoxia in glioma, and both the number of exhausted T cells and the associated
exhaustion markers (PD-L1, FOXO1, and PRDM1) correlated with HIF1α levels .
[112]
The presence of regulatory T cells (Tregs) is another contributing factor for the dysregulation of T cell
function in glioma TME [Figure 2]. Tregs are a subset of CD4 T cells that usually prevent autoimmunity
response via suppression of inflammation and maintenance of self-tolerance . Tregs (CD4+ Foxp3+)
[113]
naturally arise from thymic differentiation or are induced in the already differentiated Foxp3- CD4+ T
[114]
cells in the periphery . A recent study showed that Tregs promote CD8 T cell exhaustion and restrict
[115]
clonal diversity of tumor-infiltrating CD8 CTLs . Therefore, strategies to eliminate Tregs have been
[116]
developed to restore anti-tumor immunity in glioblastoma, including activation of glucocorticoid-induced
tumor necrosis factor-related protein (GITR). GITR is an immune checkpoint constitutively expressed in
Tregs, and its activation through ligand binding leads to the depletion of Tregs and reduced immuno-
suppression. A preclinical study by Amoozgar et al. demonstrated that targeting Tregs with anti-GITR
antibodies can relieve resistance to immunotherapy (e.g., anti-PD1) in mouse glioblastoma models .
[117]

Immunosuppression by myeloid cells
A large number of myeloid cells, such as monocytes, macrophages and MDSCs, in the glioblastoma TME
impose another great challenge for immunotherapy to function [Figure 2]. Among the tumor-infiltrating
myeloid populations in glioblastoma, TAMs play a pivotal role in tumor progression, immunosuppression,
and therapy resistance. TAMs are usually found to exhibit a tumor-promoting phenotype by producing
immune suppressive cytokines such as IL-6, IL-10, and TGF-β [104,105] , and they represent a large population of
cells with immunosuppressive function in TME. Various approaches have been proposed to target TAMs
for glioblastoma treatment. For instance, by dual targeting IL-6 and CD40, Yang et al. showed that they
could reverse TAMs-mediated tumor immunosuppression and sensitize the glioblastoma tumor to immune
checkpoint inhibitors (anti-PD1 and anti-CTLA-4) in mouse tumor models . In addition, the relatively
[118]
undifferentiated monocytic MDSCs have been found to play a significant role in glioblastoma-associated
immunosuppression. Domenis et al. demonstrate that CD14+ monocytic MDSCs were the primary
mediators of the T cell suppression induced by the GSC-derived exosomes containing various immune
suppressive cytokines .
[119]

Glioblastoma can also evade immune attack by down-regulating tumor antigen expression. Tumor antigen
loss during immunotherapy treatment, especially by CAR-T therapy, has been frequently reported .
[120]
Migrating or invading glioblastoma cells were found to have reduced expression of major histocompatibility
complex (MHC) class I and II genes, resulting in significant down-regulation of tumor antigen
presentation . Additionally, glioblastoma TME is quite a hypoxic and acidic environment. Both hypoxia
[121]
and acidosis are essential environmental cues for maintaining GSCs, especially in a HIF1α-dependent
manner [122,123] . GSCs are believed to be primarily responsible for tumor resistance to chemotherapy and
radiotherapy [124,125] . More importantly, GSCs have also been shown to have a significant role in the evasion of