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Page 697 Sharma et al. Cancer Drug Resist 2023;6:688-708 https://dx.doi.org/10.20517/cdr.2023.82

grade gliomas) and discovered a pro-tumor subset of bone marrow-derived macrophages with the
expression of a scavenger receptor MARCO . More interestingly, this subpopulation of MARCO+ TAMs
[142]
was found almost exclusively in the IDH-WT glioblastoma, and they exhibited a completely oppositive
dynamic in α-PD-1 responders vs. non- responders . Park et al. studied the immune landscape of mouse
[142]
glioblastoma with α-PD-1 treatment, and found that chemokine CCL5 induced by α-PD-1 treatment
seemed to recruit the anti-inflammatory TAMs into the glioblastoma TME . A CyToF-based high-plexing
[143]
immune profiling approach revealed that ICI-sensitivity in both human and mouse tumors was associated
with a higher number of T cells and dendritic cells (DCs) and a lower number of PD-L1 positive TAMs .
[144]

Anti-inflammatory glucocorticoids
Glucocorticoids have been used to control certain adverse effects associated with cancer immunotherapy.
Interestingly, concurrent administration of dexamethasone, a potent corticosteroid frequently used in
glioblastoma patients to decrease tumor-associated edema, has been shown to be detrimental to
immunotherapy for patients with glioblastoma . Though the clinical data in this study was limited to a
[145]
subset of patients with wild-type IDH-1 glioblastoma under α-PD-L1 treatment, the concurrent
dexamethasone diminished the response to α-PD-1 therapy in two different mouse glioma models . It is
[145]
worth mentioning that glioblastoma patients under standard (radiation plus TMZ) treatment who received
dexamethasone treatment also showed a worse outcome . However, this is likely because MGMT
[146]
promoter contains two nonconsensus glucocorticoid-responsive elements and glucocorticoids can
upregulate MGMT expression . A comprehensive study of MGMT promoter activity in glioblastoma cell
[147]
lines further clarified that dexamethasone, but not TMZ or irradiation, can induce the upregulation of
MGMT expression via a SP-1 dependent fashion , while not through altering the epigenetic status (i.e.,
[148]
methylation) of the MGMT promoter.

Role of non-coding RNAs
Long non-coding RNAs (LncRNAs) have been increasingly recognized for their essential role in cell growth,
survival, proliferation, pluripotency, and immune functions correlating to the malignant transformation of
normal cells into cancerous cells [149-151] . MALAT1, NEAT1, and H19 are among the common LncRNAs that
influence the response of glioblastoma/glioma to chemotherapeutics . Another lncRNA, LINC00021, was
[152]
significantly upregulated in glioblastoma, especially in the TMZ resistance cells or tissues, enhancing
resistance to TMZ through Notch pathway and epigenetically silencing p21 expression . A study also
[48]
showed that LncRNA SNHG15 promotes pro-glioblastoma cytokines TGF-β and lL-6 in TMZ-resistance
cells via M2-polarization of microglial cells .
[153]
Micro RNA (miRNA) also plays a role in the regulation of glioblastoma TME. One example is the
miR-15/16 cluster, which was found to be differentially expressed in various human cancers such as glioma
and prostate cancer [154,155] . In a mouse glioblastoma model, Yang et al. demonstrated that loss of miR-15/16
in mice carrying GL261 tumors resulted in improved survival, enhanced CD8 T cell infiltration, and
reduced expression of T cell exhaustion markers (PD1, TIM-3, and LAG-3) . An in vitro study by Hubner
[156]
et al. identified miR-93 as an anti-inflammatory tumor suppressor in glioblastoma . Their data showed
[157]
that miR-93 was downregulated in human glioblastoma cell lines, and restoration of miR-93 levels in
glioblastoma cells led to a decreased expression of an array of inflammatory genes (HIF-1α, MAP3K2, IL-6,
G-CSF, IL-8, LIF, and IL-1β) . More interestingly, TCGA data mining confirmed that high expression of
[157]
miR-93 was associated with better survival in the MGMT-methylated cohort of glioblastoma patients.