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Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer
Cancer Cell ( IF 50.3 ) Pub Date : 2022-05-26 , DOI: 10.1016/j.ccell.2022.05.004
Kelly Kersten 1 , Kenneth H Hu 1 , Alexis J Combes 2 , Bushra Samad 2 , Tory Harwin 3 , Arja Ray 3 , Arjun Arkal Rao 2 , En Cai 3 , Kyle Marchuk 4 , Jordan Artichoker 4 , Tristan Courau 2 , Quanming Shi 5 , Julia Belk 6 , Ansuman T Satpathy 7 , Matthew F Krummel 8
Affiliation  

T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages (TAMs) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAMs reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8+ T cells engage in unique, long-lasting, antigen-specific synaptic interactions that fail to activate T cells but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.



中文翻译:

癌症中巨噬细胞和耗尽的 CD8+ T 细胞之间的时空相互依赖性

T 细胞耗竭是抗肿瘤免疫的主要障碍。然而,肿瘤微环境(TME)中的其他免疫细胞如何导致这种功能失调状态仍然难以捉摸。在这里,我们证明TME 中肿瘤相关巨噬细胞 (TAM) 和耗竭 T 细胞 (T ex )的生物学密切相关。我们证明体内TAM 的消耗减少了肿瘤浸润 CD8 + T 细胞的耗竭程序,并重振了它们的效应潜力。相反,转录和表观遗传分析表明,T ex表达的因子可主动将单核细胞募集至 TME 并塑造其分化。使用点阵光片显微镜,我们表明 TAM 和 CD8 +T 细胞参与独特、持久、抗原特异性的突触相互作用,这种相互作用无法激活 T 细胞,但会导致它们耗尽,然后在缺氧条件下加速。空间分辨测序支持时空自我执行的正反馈回路,该回路旨在保护而不是破坏肿瘤。

更新日期:2022-05-26
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