Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin
Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin
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DOI：
10.1038/s41586-018-0812-9
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发表时间：
2019-01-17
期刊：
影响因子：
64.8
通讯作者：
Gebhardt, Thomas
中科院分区：
文献类型：
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作者：
Park, Simone L.;Buzzai, Anthony;Gebhardt, Thomas
免疫系统可以通过消除恶性细胞和防止抵抗根除的癌细胞的生长和扩散来抑制肿瘤的发展（1）。临床和实验数据表明，后一种控制模式（称为癌症免疫平衡（1））可以维持很长一段时间，可能长达几十年（2-4）。虽然癌症最常起源于上皮层，但维持这些组织区室中癌症免疫平衡的免疫应答的性质和时空动态仍不清楚。在这里，使用可移植皮肤黑色素瘤的小鼠模型（5），我们表明组织驻留记忆CD 8（+）T细胞（T-RM细胞）促进持久的黑色素瘤免疫平衡，仅限于皮肤的表皮层。一部分移植了黑色素瘤细胞的小鼠（约40%）在表皮接种后很长时间内没有肉眼可见的皮肤病变，肿瘤特异性表皮CD 69（+）CD 103（+）T-RM细胞的产生与这种自发性疾病控制相关。相比之下，缺乏T-RM形成的小鼠更容易发生肿瘤。尽管在宏观水平上没有肿瘤，但小鼠在接种后很长时间内经常在皮肤的表皮层中含有黑色素瘤细胞，活体成像显示这些细胞被T-RM细胞动态调查。与它们在黑色素瘤监测中的作用一致，在黑色素瘤接种前产生的肿瘤特异性T-RM细胞赋予了独立于再循环T细胞的对肿瘤发展的深刻保护。最后，T-RM细胞的耗竭在一部分（类似于20%）患有隐匿性黑色素瘤的小鼠中引发肿瘤生长，表明T-RM细胞可以积极抑制癌症进展。我们的研究结果表明，T-RM细胞在皮肤亚临床黑色素瘤的监测中发挥着重要作用，通过维持癌症免疫平衡。因此，它们为探索这些细胞作为未来抗癌免疫疗法的靶点提供了强大的动力。
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(1). Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium(1)-can be maintained for prolonged periods of time, possibly up to several decades(2-4). 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(5), we show that tissue-resident memory CD8(+) T cells (T-RM cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (similar to 40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69(+) CD103(+) T-RM cells correlated with this spontaneous disease control. By contrast, mice deficient in T-RM formation were more susceptible to tumour development. Despite being tumour-free 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-RM cells. Consistent with their role in melanoma surveillance, tumour-specific T-RM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of T-RM cells triggered tumour outgrowth in a proportion (similar to 20%) of mice with occult melanomas, demonstrating that T-RM cells can actively suppress cancer progression. Our results show that T-RM 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.