Hypoxia-inducible factor-1 in myeloid cells is required to protect the irradiated lung from metastasis

Recent evidence suggests that metastasis is proceeded by premetastatic niche formation where bone marrow-derived cells (BMDC), particularly those of myeloid cells (monocytes and macrophages), form clusters preparing for the arrival of cancer cells in the metastasis-prone organs such as the lung. Many molecules involved in the premetastatic niche formation has been identified, some of which include vascular endothelial growth factor (VEGF), lysyl oxidase (LOX), and S100A8. Since VEGF, LOX, and S100A8 are downstream targets of hypoxia-inducible factor (HIF), a major transcription factor stabilized under hypoxic conditions, we investigated whether HIF-1 in myeloid cells would affect the premetastatic niche formation hence metastasis to the lung. To do this, we used our novel strain of myeloid specific Hif-1α knockout (KO) mice using human S100A8, an intracellular calcium-binding protein as the myeloid promoter. We first performed bone marrow (BM) transplantation from GFP-expressing myeloid specific Hif-1α KO (hereafter denoted as Hif-1α KO) mice or GFP-expressing littermate control mice to lethally irradiated wild-type (WT) mice. Two weeks later, these mice were subcutaneously implanted for Lewis lung carcinoma (LLC) primary tumors followed by 20 Gy chest irradiation to promote the premetastatic niche formation. Primary tumors were then removed and luciferase-expressing LLC cells were intravenously injected to induce the lung metastasis. We observed to our surprise that mice receiving Hif-1α KO BM had 10-fold increase in the lung metastasis, indicating that HIF-1α in myeloid cells is required to protect the lung from the metastasis. While the total number of GFP-expressing BMDC was similar, there were significantly decreased alveolar macrophages (GFP+F4/80+CD11c+CD11b-) in the irradiated lung of mice receiving BM of Hif-1α KO BM than the littermate control mice. Because alveolar macrophages are specialized immune cells involved in phagocytosis of numerous airborne antigens, we hypothesized that HIF-1α-deficient alveolar macrophages are deficient in phagocytosis and this may be responsible for the increase in the lung metastasis. Indeed, we observed that alveolar macrophages isolated from bronchioalveolar lavage fluid of Hif-1α KO mice demonstrated a decreased phagocytic activity. We are currently investigating whether we could pharmacologically modulate phagocytic activities of alveolar macrophages to regulate the lung metastasis. In conclusion, we demonstrate that HIF-1 in alveolar macrophages is required to protect the irradiated lung from the lung metastasis, possibly in a mechanism involving phagocytosis. Citation Format: Hoibin Jeong, Beom-Ju Hong, Hyung-Seok Choi, Jung-Min Oh, G-One Ahn. Hypoxia-inducible factor-1 in myeloid cells is required to protect the irradiated lung from metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5738.