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Abstract：
Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond-there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1\'s interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3β, cytokines IFN-γ and IL-1β, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response-addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone.
摘要：
癌症免疫疗法的创新导致了几种可以破坏免疫抑制的新型免疫治疗策略的发展。一个关键的进步在于免疫检查点抑制剂(ICIs)。在患有各种治疗抗性癌症的患者中显示出显著的临床疗效和提高的生存率。这种免疫干预由针对抑制性受体的单克隆抗体组成(例如，PD-1）对细胞毒性CD8T细胞或针对相应的配体（例如，PD-L1/PD-L2）在肿瘤微环境（TME）中的癌细胞和其他细胞上过表达。然而,不是所有的癌细胞都有反应-临床反应仍然很差，免疫相关的不良反应，自适应阻力，以及一部分癌症患者对ICI的脆弱性。这一挑战展示了癌症的异质性，强调许多患者存在额外的免疫调节机制。因此,研究PD-L1与其他致癌基因和通路的相互作用对于进一步推进靶向治疗和解决耐药机制至关重要。因此，我们的目的是研究肿瘤细胞中PD-L1表达的机制，鉴于其与免疫逃避的相关性，揭示减少PD-L1表达和恢复抗肿瘤免疫反应的新机制。许多研究表明，许多癌症中Raf激酶抑制蛋白（RKIP）的上调有助于抑制恶性细胞中观察到的关键过度活跃途径。除了其在免疫应答和TME调节中的广泛参与。我们,因此,假设PD-L1在癌症免疫监视中的作用可能与肿瘤抑制因子Raf激酶抑制蛋白（RKIP）在癌细胞中的低表达水平成反比。研究了这一假设，我们发现了RKIP和PD-L1表达调控之间的几种信号串扰途径。这些途径和调节因子包括MAPK和JAK/STAT途径，GSK3β,细胞因子IFN-γ和IL-1β，Sox2和转录因子YY1和NFκB。上调PD-L1的途径抑制RKIP表达，反之亦然。在各种人类癌症中的生物信息学分析证明了PD-L1和RKIP表达之间的负相关关系及其预后作用。因此,我们怀疑RKIP的直接上调和/或靶向RKIP诱导剂与ICIs的联合使用可能导致更有针对性的抗肿瘤免疫反应-解决与PD-1/PD-L1单药治疗相关的治疗挑战.
