Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
Nature. 2019 Jan;565(7739):366-371. doi: 10.1038/s41586-018-0812-9. Epub 2018 Dec 31.
The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication. Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium-can be maintained for prolonged periods of time, possibly up to several decades. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma, we show that tissue-resident memory CD8 T cells (T cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69 CD103 T cells correlated with this spontaneous disease control. By contrast, mice deficient in T formation were more susceptible to tumour development. Despite being tumourfree at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by T cells. Consistent with their role in melanoma surveillance, tumour-specific T cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of T cells triggered tumour outgrowth in a proportion (20%) of mice with occult melanomas, demonstrating that T cells can actively suppress cancer progression. Our results show that T cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.
免疫系统可以通过消除恶性细胞和防止抵抗消除的癌细胞的生长和扩散来抑制肿瘤的发展。临床和实验数据表明，后一种控制方式——称为癌症免疫平衡——可以在很长一段时间内保持，可能长达几十年。虽然癌症最常起源于上皮层，但在这些组织隔室中维持癌症免疫平衡的免疫反应的性质和时空动态仍不清楚。在这里，我们使用可移植皮肤黑色素瘤的小鼠模型表明，组织驻留记忆 CD8 T 细胞（T 细胞）促进了持久的黑色素瘤免疫平衡，局限于皮肤的表皮层。大约 40%接种黑色素瘤细胞的小鼠在经皮接种后很长时间内仍没有肉眼可见的皮肤病变，并且肿瘤特异性表皮 CD69 CD103 T 细胞的产生与这种自发疾病控制相关。相比之下，缺乏 T 形成的小鼠更容易发生肿瘤发展。尽管在宏观水平上无肿瘤，但在接种后很长时间内，小鼠皮肤的表皮层中经常存在黑色素瘤细胞，并且活体成像显示 T 细胞对这些细胞进行了动态监测。与它们在黑色素瘤监测中的作用一致，在接种黑色素瘤之前产生的肿瘤特异性 T 细胞独立于循环 T 细胞，可显著保护免受肿瘤发展。最后，T 细胞耗竭可引发一部分（约 20%）隐匿性黑色素瘤小鼠的肿瘤生长，表明 T 细胞可积极抑制癌症进展。我们的结果表明，T 细胞通过维持癌症免疫平衡在皮肤中监测亚临床黑色素瘤方面发挥着根本作用。因此，它们为探索这些细胞作为未来癌症免疫治疗的靶点提供了强有力的动力。
