Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
RIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama 230-0045, Japan.
Biomolecules. 2023 Feb 10;13(2):348. doi: 10.3390/biom13020348.
Both natural killer T (NKT) and natural killer (NK) cells are innate cytotoxic lymphoid cells that produce inflammatory cytokines and chemokines, and their role in the innate immune response to tumors and microorganisms has been investigated. Especially, emerging evidence has revealed their status and function in the tumor microenvironment (TME) of tumor cells. Some bacteria producing NKT cell ligands have been identified to exert antitumor effects, even in the TME. By contrast, tumor-derived lipids or metabolites may reportedly suppress NKT and NK cells in situ. Since NKT and NK cells recognize stress-inducible molecules or inhibitory molecules on cancer cells, their status or function depends on the balance between inhibitory and activating receptor signals. As a recent strategy in cancer immunotherapy, the mobilization or restoration of endogenous NKT or NK cells by novel vaccines or therapies has become a focus of research. As a new biological evidence, after activation, effector memory-type NKT cells lasted in tumor-bearing models, and NK cell-based immune checkpoint inhibition potentiated the enhancement of NK cell cytotoxicity against cancer cells in preclinical and clinical trials. Furthermore, several new modalities based on the characteristics of NKT and NK cells, including artificial adjuvant vector cells, chimeric antigen receptor-expressing NK or NKT cell therapy, or their combination with immune checkpoint blockade have been developed. This review examines challenges and future directions for improving these therapies.
自然杀伤 T（NKT）细胞和自然杀伤（NK）细胞都是先天的细胞毒性淋巴细胞，它们可以产生炎症细胞因子和趋化因子，其在肿瘤和微生物固有免疫反应中的作用已经得到了研究。特别是，新出现的证据揭示了它们在肿瘤细胞肿瘤微环境（TME）中的状态和功能。已经发现一些产生 NKT 细胞配体的细菌具有抗肿瘤作用，甚至在 TME 中也是如此。相比之下，肿瘤衍生的脂质或代谢物据报道可能会抑制原位的 NKT 和 NK 细胞。由于 NKT 和 NK 细胞识别癌细胞上的应激诱导分子或抑制性分子，因此它们的状态或功能取决于抑制性和激活性受体信号之间的平衡。作为癌症免疫治疗的一种新策略，通过新型疫苗或疗法动员或恢复内源性 NKT 或 NK 细胞已成为研究的焦点。作为新的生物学证据，在激活后，效应记忆型 NKT 细胞在荷瘤模型中持续存在，并且 NK 细胞为基础的免疫检查点抑制增强了 NK 细胞对癌症细胞的细胞毒性，这在临床前和临床试验中得到了证实。此外，已经基于 NKT 和 NK 细胞的特征开发了几种新的模式，包括人工佐剂载体细胞、表达嵌合抗原受体的 NK 或 NKT 细胞治疗，或它们与免疫检查点阻断的联合治疗。这篇综述探讨了改善这些疗法的挑战和未来方向。
