Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA.
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
Cancer Cell. 2022 Jun 13;40(6):624-638.e9. doi: 10.1016/j.ccell.2022.05.004. Epub 2022 May 26.
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 (T) 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 T 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.
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促成这种功能障碍状态仍然难以捉摸。在这里，我们表明 TME 中的肿瘤相关巨噬细胞（TAM）和耗竭的 T 细胞（T）的生物学是广泛相关的。我们证明，体内耗尽 TAMs 可减少肿瘤浸润 CD8 T 细胞中的衰竭程序，并重新激发其效应功能。反过来，转录组和表观遗传分析表明，T 表达的因子可主动将单核细胞募集到 TME 中，并塑造其分化。使用晶格光片显微镜，我们表明 TAM 和 CD8 T 细胞之间存在独特的、持久的、抗原特异性的突触相互作用，这些相互作用不能激活 T 细胞，但使它们为衰竭做好准备，在缺氧条件下，衰竭会加速。空间分辨测序支持一个时空自我强化的正反馈回路，该回路与保护而不是破坏肿瘤一致。
