小W
(2024-07-01 00:01):
#paper doi：10.1038/s41590-024-01828-7 The aged tumor microenvironment limits T cell control of cancer 这是一篇探索衰老微环境是如何影响癌症浸润CD8免疫细胞的文章，通过流式细胞术 和 scRNA-seq 等技术，发现了衰老促进肿瘤生长并改变 CD8+T 细胞的命运和功能，老年 TME 中的细胞外信号驱动诱导了一种不同于 典型细胞衰竭、进化保守的与年龄相关的功能障碍 CD8+ T 细胞状态（TTAD）。同时老年肿瘤小鼠无法从治疗性 mRNA 疫苗接种中受益，而重振 cDC1 的髓系靶向免疫疗法可以改善并增强老年小鼠的 CD8+ T 细胞的免疫能力。
The aged tumor microenvironment limits T cell control of cancer
翻译
老化的肿瘤微环境限制了T细胞对癌症的控制
Abstract:
The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8 T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8 T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (T) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8 T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes T cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8 T cell immunity in aging.
翻译
癌症中与年龄相关的免疫功能障碍的病因和影响尚不完全清楚。在这里，我们发现，在老年肿瘤微环境（TME）中，CD8 T细胞的有限启动超过了限制肿瘤控制的细胞内在缺陷。衰老过程中肿瘤生长增加与 CD8 T 细胞浸润和功能减少有关。由于T细胞功能障碍的快速诱导，从年轻小鼠转移T细胞并不能恢复老年小鼠的肿瘤控制。衰老 TME 中的细胞外源信号驱动肿瘤浸润、年龄相关的功能失调 （T） 细胞状态，该状态在功能、转录和表观遗传学上与经典 T 细胞耗竭不同。老年肿瘤中自然杀伤细胞-树突状细胞-CD8 T 细胞串扰的改变会损害传统 1 型树突状细胞对 T 细胞的启动并促进 T 细胞的形成。因此，老年小鼠无法从治疗性肿瘤疫苗接种中受益。至关重要的是，髓样靶向疗法使传统的 1 型树突状细胞恢复活力，可以改善肿瘤控制并在衰老中恢复 CD8 T 细胞免疫。