Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model

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Abstract

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.

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Nguyen, Y. T. M., Fujisawa, M., Nguyen, T. B., Suehara, Y., Sakamoto, T., Matsuoka, R., … Sakata-Yanagimoto, M. (2021). Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model. Cancer Science, 112(12), 4931–4943. https://doi.org/10.1111/cas.15165

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