Pisibon Céline, Ouertani Amira, Bertolotto Corine, Ballotti Robert, Cheli Yann
Université Côte d'Azur, 06103 Nice, France.
INSERM, Centre Méditerranéen de Médecine Moléculaire, Biology and Pathologies of Melanocytes, Team1, 06200 Nice, France.
Cancers (Basel). 2021 Sep 12;13(18):4573. doi: 10.3390/cancers13184573.
The immune system is known to help fight cancers. Ten years ago, the first immune checkpoint inhibitor targeting CTLA4 was approved by the FDA to treat patients with metastatic melanoma. Since then, immune checkpoint therapies have revolutionized the field of oncology and the treatment of cancer patients. Numerous immune checkpoint inhibitors have been developed and tested, alone or in combination with other treatments, in melanoma and other cancers, with overall clear benefits to patient outcomes. However, many patients fail to respond or develop resistance to these treatments. It is therefore essential to decipher the mechanisms of action of immune checkpoints and to understand how immune cells are affected by signaling to be able to understand and overcome resistance. In this review, we discuss the signaling and effects of each immune checkpoint on different immune cells and their biological and clinical relevance. Restoring the functionality of T cells and their coordination with other immune cells is necessary to overcome resistance and help design new clinical immunotherapy strategies. In this respect, NK cells have recently been implicated in the resistance to anti-PD1 evoked by a protein secreted by melanoma, ITGBL1. The complexity of this network will have to be considered to improve the efficiency of future immunotherapies and may lead to the discovery of new immune checkpoints.
众所周知，免疫系统有助于对抗癌症。十年前，首个靶向CTLA4的免疫检查点抑制剂被美国食品药品监督管理局（FDA）批准用于治疗转移性黑色素瘤患者。从那时起，免疫检查点疗法彻底改变了肿瘤学领域以及癌症患者的治疗方式。在黑色素瘤和其他癌症中，已经研发并测试了许多免疫检查点抑制剂，它们单独使用或与其他治疗方法联合使用，总体上对患者的治疗结果有明显益处。然而，许多患者对这些治疗没有反应或产生耐药性。因此，解读免疫检查点的作用机制并了解免疫细胞如何受到信号传导的影响，对于理解和克服耐药性至关重要。在这篇综述中，我们讨论了每个免疫检查点对不同免疫细胞的信号传导和影响及其生物学和临床相关性。恢复T细胞的功能及其与其他免疫细胞的协调对于克服耐药性和帮助设计新的临床免疫治疗策略是必要的。在这方面，自然杀伤细胞（NK细胞）最近被认为与黑色素瘤分泌的一种蛋白质ITGBL1引起的抗程序性死亡蛋白1（PD1）耐药性有关。为了提高未来免疫治疗的效率，必须考虑这个网络的复杂性，这可能会导致发现新的免疫检查点。
