Inhibition of immune evasion via targeting the dysregulated EZH2-RKIP axis in cancer cells

Introduction: We have recently witnessed several milestones in the treatment of a subset of cancer patients with immunotherapy. However, the unresponsive subset is due, in part, to intrinsic factors in the cancer cells that regulate immune evasion. Thus, the identification of such resistant factors might be potential targets to restore the anti-tumor immune response. Procedure: Two dysregulated gene products were identified, the overexpressed epigenetic enhancer of zeste homologue 2 (EZH2) , a promoter of immune evasion, and the underexpressed Raf kinase inhibitor protein (RKIP), an inhibitor of immune evasion. Findings: Analyses of the signaling and cross-talk signaling pathways mediated by these two gene products established a dysregulated EZH2-RKIP axis in cancer cells that regulate immune evasion. For example, analysis of pancreatic ductal adenocarcinoma (PDAC) cancer cells overexpress EZH2 and it plays a central role in immune evasion and PDAC does not respond to check point inhibitors or various EZH2 inhibitors. Conclusion: We propose that targeting the EZH2-RKIP axis by agents that can induce RKIP expression in cancer cells will lead to downregulation of EZH2 will inhibit immune evasion and will restore the unresponsive cancer cells to respond to immunotherapy. Such agents can be used alone or in combination with other therapies. The specific targeting directly to the tumor cells and sparing normal tissues remain challenging and require novel approaches .