Re-expression of MHC-I to treat CNS cancers (IMAGE)
Caption
Figure 2: Therapeutic strategies for MHC-I re-expression in CNS cancers.
Multiple molecular and cellular pathways are involved in the regulation of MHC-I expression in cancer cells of the CNS. Tumor cells in CNS cancers often exhibit diminished MHC-I surface expression, leading to immune evasion by impairing antigen presentation to cytotoxic CD8+ T cells. (A) Ionizing radiation induces DNA double-strand breaks, leading to the accumulation of cytosolic double-stranded DNA. Cytosolic dsDNA is sensed by cGAS, which catalyzes the synthesis of the second messenger cGAMP, which binds to and activates STING at the endoplasmic reticulum, prompting its translocation and subsequent recruitment of TBK1. TBK1 phosphorylates IRF3, enabling its dimerization and nuclear translocation. In the nucleus, IRF3 drives the transcription of type I interferons, which ultimately induce MHC-I. (B) Through phosphorylation of Irf2bp1, Cdk5 restricts phosphorylation and expression of Stat1 and Nlrc5, leading to reduced MHC-I expression on the surface of cancer cells, which eventually leads to immune evasion followed by metastatic outgrowth in the brain. Targeting Cdk5 by small molecule inhibitor roscovitine may improve CNS cancers’ management. (C) A pivotal inducer of MHC-I expression is IFN-γ, a cytokine released by activated immune cells or supplied externally as a potential drug. IFN-γ binds to its receptor on tumor cells, activating the JAK1/JAK2 kinases, which phosphorylate and activate STAT1. Phosphorylated STAT1 then translocates to the nucleus, promoting expression of NLRC5 and IRF-1, master regulators of MHC-I gene transcription. Additionally, p-STAT1 can also bind to GAS element to directly initiate transcription of MHC-I heavy chains. (D) Gene therapy using AAV vectors facilitates direct delivery of MHC-I genes or transcription factors to tumor cells, enhancing MHC-I expression. (E) Autophagy blockade by chloroquine inhibits degradation of MHC-I molecules, further promoting antigen presentation. (F) Pharmacologic agents such as HDAC inhibitors (vorinostat, romidepsin, belinostat, panobinostat, givinostat), DNMT inhibitors (decitabine, azacitidine), and EZH2 inhibitors (valemetostat, tazemetostat) are depicted suppressing epigenetic silencing, thus upregulating MHC-I genes and related antigen processing components (e.g., TAPs, TAPBPs, LMPs).
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