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Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82 Page 696

immune function .
[126]
Resistance to ICIs
ICIs are currently the most prevalent immunotherapy for cancer treatment. Since the approval of the first
ICI (α-CTLA-4) by the FDA in 2011, these antibodies have been studied in an increasingly growing number
of clinical trials, including those cancers with low response rates, such as breast cancer, cervical cancer, and
brain cancer [60,127,128] . Despite the success of ICIs in treating hematopoietic cancers, the clinical trials in
glioblastoma have been underwhelming. Besides the BBB, several contributing factors that render ICIs
ineffective in glioblastoma treatment have been identified.

Low tumor mutational burden in glioblastoma tumor
Glioblastoma is generally considered an immunologically “cold” tumor type with a relatively lower tumor
mutational burden (TMB). Thus, the neoantigen levels are also lower [129,130] . Higher TMB often leads to the
formation of a greater number of neoantigens and a greater potential for T-cell repertoire against tumor-
specific antigens . TMB has been found to be correlated with the clinical outcome of cancer
[131]
immunotherapy . Compared with the immunologically “hot” tumor types such as melanoma and NSCLC,
[76]
glioblastoma shows a much lower neoantigen burden .
[132]
T cell dysfunction
Glioblastoma patients are often found to have T cell dysfunction in both CNS and peripheral blood, and T
cell exhaustion is pervasive and severe in glioblastoma TME. CD8 T cell exhaustion usually starts with the
loss of IL-2 production, a cytokine crucial for T cell proliferation, followed by loss or decreased production
of TNF-α, IFN-γ, and granzyme B . Tregs also make a significant contribution to the T cell dysfunction in
[133]
glioma. Both natural and induced Tregs can suppress the cytotoxicity of CD8 CTLs. Tregs were found to be
associated with worse prognosis in glioblastoma patients , and it seems that the natural Tregs are the
[134]
dominant subpopulation of Tregs in glioblastoma. Besides dysregulated T cell function, surprisingly,
neurons have been shown to play a role in the ICI therapy resistance in glioblastoma. A recent study
reported neuronal calmodulin-dependent kinase kinase-2 (CaMKK2) as a driver for the resistance to ICIs in
glioblastoma , in which CaMKK2 increased CD8 T cell exhaustion, reduced CD4 effector cell expansion,
[56]
and played a role in the maintenance of immunosuppressive phenotype of tumor-associated microglia .
[135]
Deficits in antigen presentation by microglia
In glioblastoma TME, antigen presentation machinery is dysregulated in almost all types of antigen-
presenting cells. The immunosuppressive microenvironment in glioblastoma leads to the downregulation of
MHC expression in microglia [136,137] . The decreased MHC expression significantly impairs the ability of
microglia to effectively present antigens, limiting the activation of other immune cells and undermining the
immune response against the tumor. Similarly, TAMs were found to be deficient in antigen presentation,
lacking costimulatory molecules CD86, CD80, and CD40 critical for T-cell activation . In fact, although
[138]
glioblastoma tumor-infiltrating dendritic cells seemed more efficient than both MΦ and microglia in
priming T-cells with exogenous antigens , data from a preclinical study demonstrated that a better anti-
[139]
tumor immunity is associated with both tumor-infiltrating dendritic cells and microglia .
[140]
TAMs
A new study using patient-derived recurrent glioblastoma tumors with neoadjuvant PD-1 antibody
treatment showed that α-PD-1 activated T cells and dendritic cells, but was unable to reverse the
immunosuppressive phenotype in TAMs . Work by Chen et al. analyzed scRNAseq data from a
[141]
combined of >19,000 individual macrophages from 66 human glioma cases (50 glioblastomas and 16 low-