The diversity of molecular states and cellular plasticity of immune cells in the glioblastoma environment is still poorly understood. Here, we performed scRNA sequencing of the immune compartment and mapped potential cellular interactions leading to an immunosuppressive microenvironment and dysfunction of T cells. Through inferring the dynamic adaptation during T cell activation, we identified three different terminal states with unique transcriptional programs. Modeling of driver genes for terminal T cell fate identified IL-10 signaling alterations in a subpopulation of HAVCR2(+) T cells. To explore in depth cellular interactions, we established an in-silico model by the integration of spatial transcriptomic and scRNA-sequencing, and identified a subset of HMOX1+ myeloid cells defined by IL10 release leading to T cell exhaustion. We found a spatial overlap between HMOX(+) myeloid and HAVCR2(+) T cells, suggesting that myeloid-lymphoid interaction causes immunosuppression present in tumor regions with enriched mesenchymal gene expression. Using human neocortical GBM model, coupled with patient-derived T cells, we confirmed that the functional interaction between myeloid and lymphoid cells, leads to a dysfunctional state of T cells. This IL-10 driven T cell exhaustion was found to be rescued by JAK/STAT inhibition. A comprehensive understanding of the cellular states and plasticity of lymphoid cells in GBM will aid towards successful immuno-therapeutic approaches.

中文翻译：

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胶质母细胞瘤相关免疫的谱系和空间定位

胶质母细胞瘤环境中免疫细胞的分子状态多样性和细胞可塑性仍然知之甚少。在这里，我们对免疫区室进行了scRNA测序，并绘制了潜在的细胞相互作用，从而导致了免疫抑制性微环境和T细胞功能障碍。通过推断T细胞活化过程中的动态适应，我们确定了具有独特转录程序的三种不同的终态。终端T细胞命运的驱动基因建模确定了HAVCR2（+）T细胞亚群中的IL-10信号改变。为了深入研究细胞相互作用，我们通过空间转录组学和scRNA测序的整合建立了计算机模型，并鉴定了由IL10释放导致T细胞衰竭的HMOX1 +髓样细胞亚群。我们发现HMOX（+）髓样和HAVCR2（+）T细胞之间存在空间重叠，这表明髓样-淋巴样相互作用导致免疫抑制存在于具有丰富的间充质基因表达的肿瘤区域。使用人类新皮层GBM模型，加上患者来源的T细胞，我们证实了髓样和淋巴样细胞之间的功能相互作用，导致T细胞功能异常。发现该IL-10驱动的T细胞衰竭可通过JAK / STAT抑制来挽救。对GBM中淋巴样细胞的细胞状态和可塑性的全面了解将有助于成功的免疫治疗方法。使用人类新皮层GBM模型，加上患者来源的T细胞，我们证实了髓样和淋巴样细胞之间的功能相互作用，导致T细胞功能异常。发现该IL-10驱动的T细胞衰竭可通过JAK / STAT抑制来挽救。对GBM中淋巴样细胞的细胞状态和可塑性的全面了解将有助于成功的免疫治疗方法。使用人类新皮层GBM模型，加上患者来源的T细胞，我们证实了髓样和淋巴样细胞之间的功能相互作用，导致T细胞功能异常。发现该IL-10驱动的T细胞衰竭可通过JAK / STAT抑制来挽救。对GBM中淋巴样细胞的细胞状态和可塑性的全面了解将有助于成功的免疫治疗方法。