Pourakbari Ramin, Hajizadeh Farnaz, Parhizkar Forough, Aghebati-Maleki Ali, Mansouri Sanaz, Aghebati-Maleki Leili
Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.
EXCLI J. 2021 Jun 9;20:1055-1085. doi: 10.17179/excli2021-3522. eCollection 2021.
Immune checkpoint pathways consist of stimulatory pathways, which can function like a strong impulse to promote T helper cells or killer CD8 cells activation and proliferation. On the other hand, inhibitory pathways keep self-tolerance of the immune response. Increasing immunological activity by stimulating and blocking these signaling pathways are recognized as immune checkpoint therapies. Providing the best responses of CD8 T cell needs the activation of T cell receptor along with the co-stimulation that is generated via stimulatory checkpoint pathways ligation including Inducible Co-Stimulator (ICOS), CD40, 4-1BB, GITR, and OX40. In cancer, programmed cell death receptor-1 (PD-1), Programmed cell death ligand-1(PD-L1) and Cytotoxic T Lymphocyte-Associated molecule-4 (CTLA-4) are the most known inhibitory checkpoint pathways, which can hinder the immune responses which have specifically anti-tumor characteristics and attenuate T cell activation and also cytokine production. The use of antagonistic monoclonal antibodies (mAbs) that block CTLA-4 or PD-1 activation is used in a variety of malignancies. It has been reported that they can lead to an increase in T cells and thereby strengthen anti-tumor immunity. Agonists of stimulatory checkpoint pathways can induce strong immunologic responses in metastatic patients; however, for achieving long-lasting benefits for the wide range of patients, efficient combinatorial therapies are required. In the present review, we focus on the preclinical and basic research on the molecular and cellular mechanisms by which immune checkpoint inhibitor blockade or other approaches with co-stimulatory agonists work together to improve T-cell antitumor immunity.
免疫检查点通路由刺激性通路组成，其作用类似于强烈的冲动，可促进辅助性T细胞或杀伤性CD8细胞的激活和增殖。另一方面，抑制性通路维持免疫反应的自身耐受性。通过刺激和阻断这些信号通路来增强免疫活性被认为是免疫检查点疗法。要使CD8 T细胞产生最佳反应，需要激活T细胞受体以及通过刺激性检查点通路连接（包括诱导性共刺激分子（ICOS）、CD40、4-1BB、糖皮质激素诱导肿瘤坏死因子受体（GITR）和OX40）产生的共刺激。在癌症中，程序性细胞死亡受体1（PD-1）、程序性细胞死亡配体1（PD-L1）和细胞毒性T淋巴细胞相关分子4（CTLA-4）是最知名的抑制性检查点通路，它们可阻碍具有特异性抗肿瘤特征的免疫反应，减弱T细胞激活以及细胞因子产生。使用阻断CTLA-4或PD-1激活的拮抗单克隆抗体（mAb）已用于多种恶性肿瘤。据报道，它们可导致T细胞增加，从而增强抗肿瘤免疫力。刺激性检查点通路的激动剂可在转移性患者中诱导强烈的免疫反应；然而，为了使广大患者获得持久益处，需要有效的联合疗法。在本综述中，我们重点关注免疫检查点抑制剂阻断或其他与共刺激激动剂联合的方法共同作用以改善T细胞抗肿瘤免疫力的分子和细胞机制的临床前及基础研究。
