SCI

22 May 2024

The aged tumor microenvironment limits T cell control of cancer

(Nature Immunology, IF: 30.5)

  • Alex C. Y. Chen, Sneha Jaiswal, Daniela Martinez1, Cansu Yerinde, Keely Ji, Velita Miranda, Megan E. Fung, Sarah A. Weiss, Maria Zschummel, Kazuhiro Taguchi, Christopher S. Garris, Thorsten R. Mempel, Nir Hacohen & Debattama R. Sen

  • CORRESPONDENCE TO: dsen@mgh.harvard.edu

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 (TTAD) 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 TTAD 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.

癌症年龄相关免疫功能障碍的病因和影响尚不完全清楚。在这里，我们发现在衰老肿瘤微环境（TME）中CD8+T细胞的有限启动在限制肿瘤控制方面超过了细胞固有缺陷。衰老中肿瘤生长的增加与CD8+T细胞浸润减少和功能减少有关。由于T细胞功能障碍的快速诱导，从年轻小鼠转移T细胞不能恢复老年小鼠的肿瘤控制。衰老TME中的细胞外源性信号驱动肿瘤浸润年龄相关功能障碍（TTAD）细胞状态，该状态在功能、转录和表观遗传学上与典型的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细胞串扰的改变削弱了传统1型树突状细胞对T细胞的启动，并促进了TTAD细胞的形成。因此，老年小鼠不能从治疗性肿瘤疫苗接种中获益。至关重要的是，骨髓靶向治疗可以重振传统的1型树突状细胞，从而改善肿瘤控制，恢复衰老过程中的CD8+T细胞免疫。

 

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