Center for Systems Biology, Massachusetts General Hospital Research Institute and Harvard Medical School, Boston, Massachusetts.
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
Cancer Immunol Res. 2022 Jan;10(1):40-55. doi: 10.1158/2326-6066.CIR-21-0326. Epub 2021 Dec 1.
Macrophages often abound within tumors, express colony-stimulating factor 1 receptor (CSF1R), and are linked to adverse patient survival. Drugs blocking CSF1R signaling have been used to suppress tumor-promoting macrophage responses; however, their mechanisms of action remain incompletely understood. Here, we assessed the lung tumor immune microenvironment in mice treated with BLZ945, a prototypical small-molecule CSF1R inhibitor, using single-cell RNA sequencing and mechanistic validation approaches. We showed that tumor control was not caused by CSF1R cell depletion; instead, CSF1R targeting reshaped the CSF1R cell landscape, which unlocked cross-talk between antitumoral CSF1R cells. These cells included IFNγ-producing natural killer and T cells, and an IL12-producing dendritic cell subset, denoted as DC, which were all necessary for CSF1R inhibitor-mediated lung tumor control. These data indicate that CSF1R targeting can activate a cardinal cross-talk between cells that are not macrophages and that are essential to mediate the effects of T cell-targeted immunotherapies and promote antitumor immunity.
肿瘤中常常富含巨噬细胞，表达集落刺激因子 1 受体（CSF1R），并与患者不良预后相关。阻断 CSF1R 信号的药物已被用于抑制促进肿瘤的巨噬细胞反应；然而，其作用机制仍不完全清楚。在这里，我们使用单细胞 RNA 测序和机制验证方法评估了用 BLZ945（一种典型的小分子 CSF1R 抑制剂）治疗的小鼠的肺肿瘤免疫微环境。我们表明，肿瘤控制不是由 CSF1R 细胞耗竭引起的；相反，CSF1R 靶向重塑了 CSF1R 细胞景观，从而开启了抗肿瘤 CSF1R 细胞之间的串扰。这些细胞包括 IFNγ 产生的自然杀伤和 T 细胞，以及一种称为 DC 的 IL12 产生树突状细胞亚群，它们都是 CSF1R 抑制剂介导的肺肿瘤控制所必需的。这些数据表明，CSF1R 靶向可以激活非巨噬细胞之间的关键串扰，这对于介导 T 细胞靶向免疫疗法的效果和促进抗肿瘤免疫至关重要。
