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Microbes & Immunity Glioblastoma therapy: Immunotherapy and inhibitors

antigens through reduced regulation and expression efficacious in the treatment of non-small-cell lung cancer
of major histocompatibility complexes (MHCs) while (NSCLC) and advanced metastatic melanoma. 53-55
simultaneously elevating immunosuppressive factors such FDA’s approval of checkpoint inhibitors pembrolizumab
as programmed cell death ligand 1 (PD-L1) and indoleamine and nivolumab in late 2014 for metastatic melanoma and
2,3-dioxygenase (IDO) cytosolic enzyme. PD-L1 ligand the subsequent approval of nivolumab in 2015 for NSCLC
activates programmed cell death protein 1 (PD-1), which initiated a cascade of growing literature into the potential
serves as an immune checkpoint receptor that inhibits the therapeutics of checkpoint inhibitors for the treatment
activity of CD8+ cytotoxic T-lymphocytes (CTLs). 36-38 IDO of GBMs. 56,57 A fundamental signature in prolonged
cytosolic enzyme is responsible for the catalysis of the rate- immunosuppression of GBMs is the upregulation of PD-L1
determining step of tryptophan-kynurenine metabolism, on monocytes and tumor cells, which leads to the further
a major biochemical pathway in T-lymphocyte immune inhibition of CD4+ and CD8+ T-lymphocytes. Sustained
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tolerance and immunosuppression. Further suppression T-cell activation, an essential characteristic of chronic
of the immune system is mediated by transforming
growth factor-beta (TGF-β), prostaglandins, as well as inflammation in cancer, further upregulates PD-L1, leading
interleukin-10, which drives signal transducer and activator to the recognition of PD-L1 on antigen-presenting cells
of transcription-3 expression in GBM cells. 39-42 The direct and GBM tumor cells. This combined mechanistic pathway
interplay between GBM and immune cells drives further leads to exhaustion, lowered T-lymphocyte proliferation,
59,60
immunosuppression by reducing the activity of natural and decreased survival. Hence, the therapeutic target of
killer cells, mediated by immunoregulatory molecules ICI is to restore T-lymphocyte activation and proliferation
human leukocyte antigen (HLA)-A and HLA-G. 43-45 of antitumor activity through the blockade of PD-L1 and
CTLA-4 immune checkpoints. 61-63
Although the driving mechanisms of immunosuppression
by GBM cells remain largely unknown, the most frequent 5.3. Vaccine therapy
mediators of such systemic and local immune escape appear Vaccine therapy is another area of promising
to revolve around myeloid cells. In particular, CD45+/ immunotherapeutics in the treatment of GBMs. Predicated
CD11b+ myeloid cells are the principal inflammatory on the observation that GBM cells do not metastasize
cells responsible for the infiltration of GBM cells. Hence, outside the brain, vaccine therapies aim to induce a
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molecular strategies aimed at exploiting myeloid cells to strong antitumor immunogenic response by activating
induce an antitumor immune response and lower the the adaptive immune system. 64,65 Vaccines, as “active”
biochemical dominance of immunosuppressive ligands interventions, aim to precipitate a robust response from the
present a promising approach in immunotherapies for patient’s immune system and can either be cell-based, such
glioblastoma. For instance, delivery of adjuvants such as as pulsing dendritic cells (DCs), or non-cell-based such
toll-like receptor agonists and granulocyte-macrophage as heat shock protein (HSP)-based vaccines. DC-based
colony-stimulating factor and neutralization of TGF-β vaccines rely on the pulsation of glioblastoma antigens
activity through myeloid cells has shown promise in onto patient-derived DCs, allowing for the presentation
counteracting the immunosuppressive effects of GBM. 47
of multiple antigens. DC-based vaccines offer a promising
5.2. Immune checkpoint inhibitors (ICIs) therapeutic approach, given that GBM tumor cells display
substantial intra-tumoral heterogeneity. 66-68
Out of all the contemporary advances in immunotherapy
over the past decade, ICIs have substantially altered our As intracellular chaperones, HSPs aid protein
conception of immunotherapy for various cancers in localization, folding, and stability. In commonly observed
which conventional therapies have failed. ICIs induce tumor microenvironments of GBM, hypoxia, hypothermia,
an antineoplastic immune response by suppressing inflammation, and substantial oxidative load lead to the
co-inhibitory receptors, ligands, and mechanistic pathways activation of HSP. Hence, neoplastic cells rely on HSP
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activated by GBM cells to deactivate the T-lymphocyte for survival. There is also evidence of transcriptional
response against the tumor cells. 48-50 More importantly, upregulation of HSPs during cancer, as observed in the
the administration of ICIs, although not entirely deprived increased translation of abnormal protein products. In
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of treatment-related cytotoxicity, has prompted long- the context of GBM, HSP70 and HSP90 serve as critical
lasting and systemic remissions over several years. 51,52 molecular chaperones in the initiation and proliferation
For instance, inhibitors for immune checkpoints such as of tumor signaling pathways. Furthermore, HSP70 and
anti-PD-1/PD-L1 ICIs and anti-cytotoxic T-lymphocyte- HSP90 bind and display tumor-specific antigens. Hence,
associated antigen 4 (CTLA-4) have proven to be highly the therapeutic strategy of HSP vaccines relies on their

Volume 2 Issue 4 (2025) 135 doi: 10.36922/mi.5075