Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, USA.
Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, Saint Louis, MO, USA.
Oncogene. 2021 Jul;40(27):4521-4537. doi: 10.1038/s41388-021-01880-9. Epub 2021 Jun 12.
Natural killer (NK) and natural killer T (NKT) cells are two important cell subsets of the innate immune system. NK and NKT cells share many phenotypes and functions for anti-tumor immunity; however, the dynamic changes in phenotypes and functional interactions within the tumor microenvironment during tumor development and progression are unknown. Here we report that NK and NKT cells have distinct properties, metabolic profiles, and functions during tumor development. Using the mouse E0771 breast cancer and B16 melanoma models, we found that both NK and NKT cells are dynamically involved in the immune responses to cancer but have distinct distributions and phenotypic profiles in tumor sites and other peripheral organs during the course of tumor development and progression. In the early stages of tumor development, both NK and NKT cells exhibit effector properties. In the later cancer stages, NK and NKT cells have impaired cytotoxic capacities and dysfunctional states. NK cells become senescent cells, while NKT cells, other than invariant NKT (iNKT) cells, are exhausted in the advanced cancers. In contrast, iNKT cells develop increases in activation and effector function within the breast tumor microenvironment. In addition, senescent NK cells have heightened glucose and lipid metabolism, but exhausted NKT cells display unbalanced metabolism in tumor microenvironments of both breast cancer and melanoma tumor models. These studies provide a better understanding of the dynamic and distinct functional roles of NK and NKT cells in anti-tumor immunity, which may facilitate the development of novel immunotherapies targeting NK and NKT cells for cancer treatment.
自然杀伤 (NK) 和自然杀伤 T (NKT) 细胞是先天免疫系统的两个重要细胞亚群。NK 和 NKT 细胞在抗肿瘤免疫方面具有许多表型和功能；然而，在肿瘤发展和进展过程中，肿瘤微环境中表型和功能相互作用的动态变化尚不清楚。在这里，我们报告 NK 和 NKT 细胞在肿瘤发展过程中有不同的特性、代谢特征和功能。使用小鼠 E0771 乳腺癌和 B16 黑色素瘤模型，我们发现 NK 和 NKT 细胞在肿瘤免疫反应中都具有动态作用，但在肿瘤发展和进展过程中，它们在肿瘤部位和其他外周器官中的分布和表型特征不同。在肿瘤发展的早期阶段，NK 和 NKT 细胞都表现出效应器特性。在晚期癌症中，NK 和 NKT 细胞的细胞毒性能力受损，功能失调。NK 细胞成为衰老细胞，而 NKT 细胞（除了不变自然杀伤 T (iNKT) 细胞外）在晚期癌症中处于耗竭状态。相比之下，iNKT 细胞在乳腺肿瘤微环境中激活和效应功能增加。此外，衰老的 NK 细胞具有更高的葡萄糖和脂质代谢，但在乳腺癌和黑色素瘤肿瘤模型的肿瘤微环境中，耗竭的 NKT 细胞显示出代谢失衡。这些研究提供了对 NK 和 NKT 细胞在抗肿瘤免疫中的动态和独特功能作用的更好理解，这可能有助于开发针对 NK 和 NKT 细胞的新型免疫疗法来治疗癌症。
