Department of Experimental Immunology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan.
Int Immunol. 2022 Oct 5;34(11):555-561. doi: 10.1093/intimm/dxac024.
Cancer immunotherapy utilizes our immune system to attack cancer cells and is an extremely promising strategy for cancer treatment. Although immune-checkpoint blockade, such as anti-PD-1 (programmed cell death 1) antibody, has demonstrated significant enhancement of anti-tumor immunity and has induced notable clinical outcomes, its response rates remain low, and adverse effects are always a matter of concern; therefore, new targets for cancer immunotherapy are always desired. In this situation, new concepts are needed to fuel the investigation of new target molecules for cancer immunotherapy. We propose that CD69 is one such target molecule. CD69 is known to be an activation marker of leukocytes and is also considered a crucial regulator of various immune responses through its interacting proteins. CD69 promotes T-cell retention in lymphoid tissues via sphingosine-1-phosphate receptor 1 (S1P1) internalization and also plays roles in the pathogenesis of inflammatory disorders through interacting with its functional ligands Myl9/12 (myosin light chains 9, 12a and 12b). In anti-tumor immunity, CD69 is known to be expressed on T cells in the tumor microenvironment (TME) and tumor-draining lymph nodes (TDLNs). We revealed that CD69 negatively regulates the effector function of intratumoral T cells and importantly controls the 'exhaustion' of CD8 T cells. In addition, we and others showed that either CD69 deficiency or the administration of anti-CD69 monoclonal antibody enhances anti-tumor immunity. Thus, CD69 is an attractive target for cancer immunotherapy.
癌症免疫疗法利用我们的免疫系统来攻击癌细胞，是一种极具前景的癌症治疗策略。尽管免疫检查点阻断，如抗 PD-1（程序性细胞死亡 1）抗体，已经证明了对肿瘤免疫的显著增强，并诱导了显著的临床结果，但它的反应率仍然很低，而且不良反应一直是人们关注的问题；因此，人们总是希望有新的癌症免疫治疗靶点。在这种情况下，需要新概念来推动对癌症免疫治疗新靶点分子的研究。我们提出 CD69 就是这样的一个靶点分子。CD69 是众所周知的白细胞激活标志物，通过其相互作用蛋白，也被认为是各种免疫反应的关键调节因子。CD69 通过鞘氨醇-1-磷酸受体 1（S1P1）内化促进 T 细胞在淋巴组织中的保留，并且通过与其功能配体 Myl9/12（肌球蛋白轻链 9、12a 和 12b）相互作用，在炎症性疾病的发病机制中发挥作用。在抗肿瘤免疫中，CD69 已知在肿瘤微环境（TME）和肿瘤引流淋巴结（TDLNs）中的 T 细胞上表达。我们揭示 CD69 负调节肿瘤内 T 细胞的效应功能，并重要地控制 CD8 T 细胞的“耗竭”。此外，我们和其他人表明，CD69 缺乏或施用抗 CD69 单克隆抗体增强了抗肿瘤免疫。因此，CD69 是癌症免疫治疗的一个有吸引力的靶点。
