Department of Hematology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Cancer Sci. 2021 Dec;112(12):4931-4943. doi: 10.1111/cas.15165. Epub 2021 Oct 28.
Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss-of-function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2-deficient immune cells in tumor tissues. Myeloid-specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single-cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2-deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2-deficient mice relative to controls. Finally, treatment of Tet2-deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2-mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2-mutated clonal hematopoiesis.
据报道，携带体细胞突变的免疫细胞浸润实体瘤患者的肿瘤组织，并伴有克隆性造血。在实体瘤的克隆性造血中，经常观察到功能丧失性 TET2 突变。在这里，我们使用小鼠肺癌模型评估了 Tet2 缺陷免疫细胞在肿瘤组织中的活性。与对照组相比，髓系特异性 Tet2 缺陷增强了小鼠的肿瘤生长。对浸润肿瘤的免疫细胞进行单细胞测序分析显示，Tet2 缺陷髓系亚群中相对高表达 S100a8/S100a9。反过来，用 S100a8/S100a9 处理癌细胞促进了 Vegfa 的产生，导致 Tet2 缺陷小鼠的肿瘤血管明显增加，与对照组相比。最后，用针对 Emmprin（一种已知的 S100a8/S100a9 受体）的抗体治疗 Tet2 缺陷小鼠，抑制了肿瘤生长。这些数据表明，源自 TET2 突变克隆性造血的免疫细胞通过促进肿瘤血管生成加剧了肺癌的进展，并且可能为 TET2 突变克隆性造血的肺癌患者提供新的治疗靶点。
