The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.
近年来，癌症免疫疗法治疗取得了重要里程碑。在这些免疫治疗策略中，美国食品药品监督管理局已批准数种检查点抑制剂，主要为抗程序性死亡蛋白-1及其配体PD-L1/2的单克隆抗体，用于治疗对免疫疗法无应答的多种癌症。此类治疗使部分患者获得显著临床响应并延长了生存期。然而，并非所有患者都对检查点抑制剂产生应答，这归因于多种免疫抵抗机制。其中一种机制是：除CD8 T细胞表达的PD-1外，还存在其他抑制性受体，如淋巴细胞活化基因3、T细胞免疫球蛋白黏蛋白3以及具有Ig和ITIM结构域的T细胞免疫受体。这些抑制性受体可能在已获批检查点抑制剂存在的情况下仍保持活性。显然，使用传统抗体同时阻断所有此类抑制性受体在临床上具有挑战性。为克服这一难题，我们致力于靶向可能参与多个抑制性受体分子调控的潜在转录因子。研究发现转录因子阴阳调节因子1可调控PD-1、LAG-3和TIM3的表达。因此我们提出假设：靶向CD8 T细胞中的YY1应能抑制这些受体的表达，从而通过肿瘤细胞相应配体阻止这些受体对抗肿瘤CD8 T细胞的失活作用。该策略应能防止免疫逃逸，进而抑制肿瘤生长。此外，该策略对已获批检查点抑制剂无应答的癌症患者亚群可能尤为有效。本综述通过探讨YY1对LAG-3的调控机制，论证靶向YY1作为预防癌症免疫逃逸替代疗法的潜在价值。我们系统阐述了YY1与LAG-3表达的分子调控机制、YY1对LAG-3的直接调控作用、靶向YY1规避免疫逃逸的多重策略及其临床挑战。通过生物信息学分析，我们证实LAG-3、YY1及PD-L1在多种癌症中过表达，其与免疫浸润存在相关性，且LAG-3启动子区高甲基化与更佳总生存期相关。因此，靶向CD8 T细胞中的YY1将恢复抗肿瘤免疫应答并促使肿瘤消退。值得注意的是，除通过靶向CD8 T细胞中YY1抑制抑制性受体表达外，我们还建议靶向肿瘤细胞中过表达的YY1，这将同时抑制PD-L1表达及其他YY1相关促肿瘤活性。
肿瘤(癌症)患者之家