MD Student, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran.
Biomed Pharmacother. 2022 Dec;156:113906. doi: 10.1016/j.biopha.2022.113906. Epub 2022 Oct 25.
Tumor microenvironment (TME) takes critical roles in tumor resistance to immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1). Cancer stem cells (CSCs) are one of the key components of TME that play important roles in immunoregulation and therapy resistance. CSCs suppress CD8 T cell infiltration, and promote recruitment of type 2 macrophages (M2) and the activity of type 2 neutrophils (N2). There is a positive association between CSC expansion with high PD-L1 expression in TME, and the expression of PD-L1 is higher in CSCs than cancer cells. PD-L1 expression in metastatic cancer cells induces a dedifferentiation program through stimulating an epithelial-mesenchymal transition (EMT) profile, thereby replenishing CSC proportion inside tumor. Conversion from EMT to mesenchymal-epithelial transition (MET) downregulates PD-L1 expression on CSCs and non-CSCs and increases ICI efficacy. There is an evidence of CSC replenishment secondary to the anti-PD-1 therapy. Targeting CSCs is, in fact, a key step in effective tumor breakdown and reducing tumor recurrence after immunotherapy. A number of signaling are involved in CSC enrichment within tumor area, among them a key focus is over transforming growth factor-β (TGF-β). TGF-β induces a dedifferentiation program, and its activity as a bridge between EMT with increased PD-L1 level rationalizes application of dual TGF-β/anti-PD-L1 inhibitors as an effective strategy for reinvigorating immunoactivities in patients under ICI therapy. In this review, we aimed to discuss about connections between CSCs with immune ecosystem of tumor and the impact of such interactions on cancer responses to ICI therapy.
肿瘤微环境（TME）在肿瘤对免疫检查点抑制剂（ICIs）的耐药中起着关键作用，包括抗程序性死亡-1（PD-1）或抗程序性死亡配体 1（PD-L1）。癌症干细胞（CSC）是 TME 的关键组成部分之一，在免疫调节和治疗耐药中发挥重要作用。CSC 抑制 CD8 T 细胞浸润，并促进 2 型巨噬细胞（M2）和 2 型中性粒细胞（N2）的募集。CSC 扩增与 TME 中高 PD-L1 表达之间存在正相关，并且 CSC 中的 PD-L1 表达高于癌细胞。转移性癌细胞中的 PD-L1 表达通过刺激上皮-间充质转化（EMT）谱诱导去分化程序，从而在肿瘤内补充 CSC 比例。从 EMT 到间质-上皮转化（MET）的转化下调 CSC 和非 CSC 上的 PD-L1 表达，并增加 ICI 疗效。有证据表明，抗 PD-1 治疗后会出现 CSC 补充。靶向 CSC 实际上是有效破坏肿瘤和减少免疫治疗后肿瘤复发的关键步骤。许多信号通路参与了肿瘤内 CSC 的富集，其中一个关键焦点是转化生长因子-β（TGF-β）。TGF-β 诱导去分化程序，其作为 EMT 与 PD-L1 水平升高之间的桥梁的活性为双重 TGF-β/抗 PD-L1 抑制剂的应用提供了合理化依据，作为一种有效策略，可重新激活接受 ICI 治疗患者的免疫活性。在这篇综述中，我们旨在讨论 CSC 与肿瘤免疫生态系统之间的联系，以及这种相互作用对癌症对 ICI 治疗反应的影响。
