Dutta Shovan, Ganguly Anirban, Chatterjee Kaushiki, Spada Sheila, Mukherjee Sumit
The Center for Immunotherapy & Precision Immuno-Oncology (CITI), Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Biochemistry, All India Institute of Medical Sciences, Deoghar 814152, India.
Biology (Basel). 2023 Jan 30;12(2):218. doi: 10.3390/biology12020218.
Immune checkpoint blockade (ICB) has emerged as a novel therapeutic tool for cancer therapy in the last decade. Unfortunately, a small number of patients benefit from approved immune checkpoint inhibitors (ICIs). Therefore, multiple studies are being conducted to find new ICIs and combination strategies to improve the current ICIs. In this review, we discuss some approved immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and also highlight newer emerging ICIs. For instance, HLA-E, overexpressed by tumor cells, represents an immune-suppressive feature by binding CD94/NKG2A, on NK and T cells. NKG2A blockade recruits CD8+ T cells and activates NK cells to decrease the tumor burden. NKG2D acts as an NK cell activating receptor that can also be a potential ICI. The adenosine A2A and A2B receptors, CD47-SIRPα, TIM-3, LAG-3, TIGIT, and VISTA are targets that also contribute to cancer immunoresistance and have been considered for clinical trials. Their antitumor immunosuppressive functions can be used to develop blocking antibodies. PARPs, mARTs, and B7-H3 are also other potential targets for immunosuppression. Additionally, miRNA, mRNA, and CRISPR-Cas9-mediated immunotherapeutic approaches are being investigated with great interest. Pre-clinical and clinical studies project these targets as potential immunotherapeutic candidates in different cancer types for their robust antitumor modulation.
在过去十年中，免疫检查点阻断（ICB）已成为一种新型的癌症治疗工具。不幸的是，只有少数患者能从已获批的免疫检查点抑制剂（ICI）中获益。因此，目前正在进行多项研究，以寻找新的ICI和联合策略来改进现有的ICI。在这篇综述中，我们讨论了一些已获批的免疫检查点，如程序性死亡配体1（PD-L1）、程序性死亡受体1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4），同时也重点介绍了一些新出现的ICI。例如，肿瘤细胞过度表达的人类白细胞抗原E（HLA-E）通过与自然杀伤细胞（NK）和T细胞上的CD94/NKG2A结合，表现出免疫抑制特性。阻断NKG2A可募集CD8+T细胞并激活NK细胞，从而减轻肿瘤负担。NKG2D作为一种NK细胞激活受体，也可能成为潜在的ICI。腺苷A2A和A2B受体、CD47-信号调节蛋白α（SIRPα）、T细胞免疫球蛋白和粘蛋白结构域3（TIM-3）、淋巴细胞激活基因3（LAG-3）、T细胞免疫受体Ig和ITIM结构域（TIGIT）以及VISTA等靶点也与癌症免疫抵抗有关，并已被考虑用于临床试验。它们的抗肿瘤免疫抑制功能可用于开发阻断抗体。聚（ADP-核糖）聚合酶（PARP）、膜结合型雄激素受体（mART）和B7-H3也是其他潜在的免疫抑制靶点。此外，人们对微小RNA（miRNA）、信使核糖核酸（mRNA）和CRISPR-Cas9介导的免疫治疗方法也进行了深入研究。临床前和临床研究表明，这些靶点因其强大的抗肿瘤调节作用，有望成为不同癌症类型的潜在免疫治疗候选药物。
