During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+T cells. One mechanism by which the anti-tumor CD8+T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response.
过去十年间，我们在多种耐药性癌症治疗领域见证了多项里程碑式进展，其中免疫治疗策略已被证实优于化疗、放疗等传统治疗方案。该疗法通过癌细胞表达的肿瘤相关抗原或新抗原激活宿主免疫应答，由免疫毒性CD8+T细胞特异性靶向杀伤肿瘤细胞，从而在某些癌症中实现肿瘤消退并延长患者生存期。然而部分癌症可能因抗肿瘤CD8+T细胞失活而产生治疗抵抗。抗肿瘤CD8+T细胞功能失调的机制之一，是通过表达程序性死亡配体-1（PD-L1）的肿瘤细胞（或肿瘤微环境中的其他细胞）激活抑制性受体程序性死亡-1（PD-1）。因此，通过特异性单克隆抗体阻断PD-1/PD-L1相互作用可恢复CD8+T细胞功能，实现肿瘤消退。基于此，美国食品药品监督管理局已批准多种作为免疫检查点抑制剂的检查点抗体，其在转移性黑色素瘤、非小细胞肺癌等耐药性癌症中的临床应用显示出显著的临床应答。 我们探索了通过靶向致癌转录因子阴阳1（YY1）来抑制肿瘤细胞PD-L1表达的新策略，该因子在多种癌症中均存在过表达现象。研究发现YY1在转录、转录后及翻译后水平调控PD-L1表达，从而恢复CD8+T细胞的抗肿瘤功能。我们通过生物信息学分析进一步验证了YY1与PD-L1在癌症中的关联机制。除调控PD-L1外，YY1还具有多重抗癌活性，包括调控细胞增殖与活力、侵袭、上皮-间质转化、转移及化疗-免疫抵抗等过程。因此，靶向YY1可通过多重抗肿瘤机制显著抑制癌症的致癌活性。本文提出多种选择性靶向YY1的治疗策略，为治疗无应答癌症表型提供了前景广阔的新型治疗方案。这些发现凸显了YY1与PD-L1（CD274）在癌症进展和治疗应答中独特的调控作用。
Regulation of PD-L1 Expression by YY1 in Cancer: Therapeutic Efficacy of Targeting YY1
肿瘤(癌症)患者之家