Recent advances in the treatment of various cancers have resulted in the adaptation of several novel immunotherapeutic strategies. Notably, the recent intervention through immune checkpoint inhibitors has resulted in significant clinical responses and prolongation of survival in patients with several therapy-resistant cancers (melanoma, lung, bladder, etc.). This intervention was mediated by various antibodies directed against inhibitory receptors expressed on cytotoxic T-cells or against corresponding ligands expressed on tumor cells and other cells in the tumor microenvironment (TME). However, the clinical responses were only observed in a subset of the treated patients; it was not clear why the remaining patients did not respond to checkpoint inhibitor therapies. One hypothesis stated that the levels of PD-L1 expression correlated with poor clinical responses to cell-mediated anti-tumor immunotherapy. Hence, exploring the underlying mechanisms that regulate PD-L1 expression on tumor cells is one approach to target such mechanisms to reduce PD-L1 expression and, therefore, sensitize the resistant tumor cells to respond to PD-1/PD-L1 antibody treatments. Various investigations revealed that the overexpression of the transcription factor Yin Yang 1 (YY1) in most cancers is involved in the regulation of tumor cells’ resistance to cell-mediated immunotherapies. We, therefore, hypothesized that the role of YY1 in cancer immune resistance may be correlated with PD-L1 overexpression on cancer cells. This hypothesis was investigated and analysis of the reported literature revealed that several signaling crosstalk pathways exist between the regulations of both YY1 and PD-L1 expressions. Such pathways include p53, miR34a, STAT3, NF-kB, PI3K/AKT/mTOR, c-Myc, and COX-2. Noteworthy, many clinical and pre-clinical drugs have been utilized to target these above pathways in various cancers independent of their roles in the regulation of PD-L1 expression. Therefore, the direct inhibition of YY1 and/or the use of the above targeted drugs in combination with checkpoint inhibitors should result in enhancing the cell-mediated anti-tumor cell response and also reverse the resistance observed with the use of checkpoint inhibitors alone.

在各种癌症的治疗中的最新进展已导致对几种新颖的免疫治疗策略的适应。值得注意的是，最近通过免疫检查点抑制剂进行的干预已导致患有数种具有治疗耐药性的癌症（黑色素瘤，肺癌，膀胱癌等）的患者获得了显着的临床反应并延长了生存期。这种干预是由针对细胞毒性T细胞上表达的抑制性受体或针对肿瘤微环境（TME）中肿瘤细胞和其他细胞上表达的相应配体的各种抗体介导的。但是，仅在一部分接受治疗的患者中观察到了临床反应。尚不清楚为什么其余患者对检查点抑制剂疗法没有反应。一种假设表明，PD-L1表达水平与对细胞介导的抗肿瘤免疫疗法的不良临床反应相关。因此，探索调节肿瘤细胞上PD-L1表达的潜在机制是靶向此类机制以降低PD-L1表达的方法，因此使耐药肿瘤细胞对PD-1 / PD-L1抗体治疗敏感。各种研究表明，在大多数癌症中转录因子尹扬1（YY1）的过表达与肿瘤细胞对细胞介导的免疫疗法的抗性的调节有关。因此，我们假设YY1在癌症免疫抵抗中的作用可能与PD-L1在癌细胞上的过度表达有关。对该假设进行了研究，对报道文献的分析表明，YY1和PD-L1表达的调控之间存在着几种信号串扰通路。此类途径包括p53，miR34a，STAT3，NF-kB，PI3K / AKT / mTOR，c-Myc和COX-2。值得注意的是，许多临床和临床前药物已被用于靶向上述各种癌症途径，而与它们在PD-L1表达调节中的作用无关。因此，YY1的直接抑制和/或上述目标药物与检查点抑制剂的组合使用应导致增强细胞介导的抗肿瘤细胞反应，并且还可以逆转单独使用检查点抑制剂所观察到的耐药性。PI3K / AKT / mTOR，c-Myc和COX-2。值得注意的是，许多临床和临床前药物已被用于靶向上述各种癌症途径，而与它们在PD-L1表达调节中的作用无关。因此，YY1的直接抑制和/或上述目标药物与检查点抑制剂的组合使用应导致增强细胞介导的抗肿瘤细胞反应，并且还可以逆转单独使用检查点抑制剂所观察到的耐药性。PI3K / AKT / mTOR，c-Myc和COX-2。值得注意的是，许多临床和临床前药物已被用于靶向上述各种癌症途径，而与它们在PD-L1表达调节中的作用无关。因此，YY1的直接抑制和/或上述目标药物与检查点抑制剂的组合使用应导致增强细胞介导的抗肿瘤细胞反应，并且还可以逆转单独使用检查点抑制剂所观察到的耐药性。