Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
J Immunother Cancer. 2024 Oct 31;12(10):e009934. doi: 10.1136/jitc-2024-009934.
Immune checkpoint blockade, which enhances the reactivity of T cells to eliminate cancer cells, has emerged as a potent strategy in cancer therapy. Besides T cells, natural killer (NK) cells also play an indispensable role in tumor surveillance and destruction. NK Group 2 family of receptor A (NKG2A), an emerging co-inhibitory immune checkpoint expressed on both NK cells and T cells, mediates inhibitory signal via interaction with its ligand human leukocyte antigen-E (HLA-E), thereby attenuating the effector and cytotoxic functions of NK cells and T cells. Developing antibodies to block NKG2A, holds promise in restoring the antitumor cytotoxicity of NK cells and T cells. In this review, we delve into the expression and functional significance of NKG2A and HLA-E, elucidating how the NKG2A-HLA-E axis contributes to tumor immune escape via signal transduction mechanisms. Furthermore, we provide an overview of clinical trials investigating NKG2A blockade, either as monotherapy or in combination with other therapeutic antibodies, highlighting the responses of the immune system and the clinical benefits for patients. We pay special attention to additional immune co-signaling molecules that serve as potential targets on both NK cells and T cells, aiming to evoke more robust immune responses against cancer. This review offers an in-depth exploration of the NKG2A-HLA-E pathway as a pivotal checkpoint in the anti-tumor responses, paving the way for new immunotherapeutic strategies to improve cancer patient outcomes.
免疫检查点阻断，通过增强 T 细胞的反应性来消除癌细胞，已成为癌症治疗的一种有效策略。除了 T 细胞，自然杀伤 (NK) 细胞在肿瘤监测和破坏中也起着不可或缺的作用。NK 细胞群 2 家族受体 A (NKG2A) 是一种新兴的共抑制免疫检查点，表达于 NK 细胞和 T 细胞上，通过与配体人类白细胞抗原-E (HLA-E) 的相互作用传递抑制信号，从而削弱 NK 细胞和 T 细胞的效应和细胞毒性功能。开发阻断 NKG2A 的抗体有望恢复 NK 细胞和 T 细胞的抗肿瘤细胞毒性。在这篇综述中，我们深入探讨了 NKG2A 和 HLA-E 的表达和功能意义，阐明了 NKG2A-HLA-E 轴如何通过信号转导机制促进肿瘤免疫逃逸。此外，我们还概述了研究 NKG2A 阻断的临床试验，无论是作为单一疗法还是与其他治疗性抗体联合使用，重点介绍了免疫系统的反应和患者的临床获益。我们特别关注 NK 细胞和 T 细胞上作为潜在靶点的其他免疫共信号分子，旨在引发针对癌症的更强大免疫反应。这篇综述深入探讨了 NKG2A-HLA-E 通路作为抗肿瘤反应的关键检查点，为改善癌症患者预后的新免疫治疗策略铺平了道路。
