Effect of the RKIP-SNAIL-YY1 axis on immune evasion in GBM.

Abstract

e14033 Background: Glioblastoma multifome (GBM)is an aggressiveand malignant form of brain cancer, constituting approximately 12-15 % of all primary brain tumors. The prognosis of GBM remains poor despite a multimodal treatment approach; therefore, there remains an urgent need for a novel and effective therapeutic approach. There exist several gene products that regulate immune evasion in GBM and, thus, may be targeted to restore the anti-tumor response in GBM. We hypothesize that the dysregulated RKIP-SNAIL-YY1 axis in GBM is involved in the pathogenesis and immune evasion of GBM. The existence of such an axis would make it amenable to therapeutic targeting. Methods: Delineation of the cross-talk signaling pathways mediated by each of the axis gene products; analyses of immune evasion parameters regulated by each gene product; validation by bioinformatic analyses of the presence of a dysregulated axis in GBM; and various means targeting gene products in the axis. Results: The expression levels of SNAIL and YY1 are upregulated while RKIP expression is downregulated in GBM. Previous findings from our laboratory and others have demonstrated that YY1 regulates the metastasis inducer SNAIL expression and, in turn, SNAIL suppresses the metastasis suppressor and immune inducer RKIP expression. In turn, RKIP inhibits both YY1 and SNAIL via its inhibition of NF-KB-induced transcription of both YY1 and SNAIL. These findings are the result of cross-talk signaling pathways, including the RAF/MEK /ERK, NF-kB, PI3K/AKT pathways. These findings supported the presence of a dysregulated RKIP-SNAIL-YY1 axis. Bioinformatic analyses will be performed to validate the axis. Both YY1 and SNAIL regulate PD-L1 expression and an immunosuppressive TME whereas RKIP expression reverses the immunosuppressive phenotype and facilitates GBM’s response to immunotherapy. Conclusions: The dysregulated RKIP-SNAIL-YY1 axis in GBM plays a pivotal role in the pathogenesis of GBM and resistance to current therapeutics and immunotherapy. Hence, targeting any of the gene products in the axis will negatively affect the other two gene products. Various means are proposed for targeting each gene product including small molecular inhibitors, mRNA and lncRNA, nanotechnology, PROTAC, etc. These need to be examined in preclinical models for effectiveness and toxicities as well as addressing various challenges for the specific and direct targeting of the cancer cells.