Abstract
PurposeThe incidence of head and neck squamous cell carcinomas (HNSCC) is increasing worldwide, especially when triggered by the human papilloma virus (HPV). Radiotherapy has immune-modulatory properties, but the role of macrophages present in HNSCC and having contact with irradiated tumor cells remains unclear. The influence of irradiated (2 × 5Gy) HNSCC cells on the (re-)polarization and phagocytosis of human macrophages, either non-polarized or with a more M1 or M2 phenotype, was therefore investigated.MethodsHuman monocytes were differentiated with the hematopoietic growth factors M‑CSF (m) or GM-CSF (g) and additionally pre-polarized with either interleukin (IL)-4 and IL-10 or interferon (IFN)-γ and lipopolysaccharides (LPS), respectively. Subsequently, they were added to previously irradiated (2 × 5Gy) and mock-treated HPV-positive (UD-SCC-2) and HPV-negative (Cal33) HNSCC cells including their supernatants.ResultsThe HNSCC cells treated with hypofractionated irradiation died via apoptosis and were strongly phagocytosed by M0m and M2 macrophages. M0g and M1 macrophages phagocytosed the tumor cells to a lesser extent. Irradiated HNSCC cells were better phagocytosed by M1 macrophages compared to mock-treated controls. The polarization status of the macrophages was not significantly changed, except for the expression of CD206 on M2 macrophages, which was reduced after phagocytosis of irradiated HPV-negative cells. Further, a significant increase in the uptake of irradiated HPV-positive cells by M0g macrophages when compared to HPV-negative cells was observed.ConclusionHNSCC cells treated with hypofractionated irradiation foster phagocytosis by anti-tumorigenic M1 macrophages. The data provide the first evidence on the impact of the HPV status of HNSCC cells on the modulation of the macrophage response to irradiated tumor cells.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 890,000 new cases every year [1]
Considering that tumorassociated macrophages (TAMs) contribute to the formation of an immunosuppressed state within the tumor microenvironment (TME), one of the therapeutic strategies targeting TAMs is reeducating TAMs to an antitumor phenotype, such as promoting the phagocytosis ability of macrophages [22, 76]
To investigate the phagocytosis and subsequentpolarization of differentiated and pre-polarized macrophages in vitro, human monocytes were differentiated for 7 days with the hematopoietic growth factors macrophage-stimulating factor (M-CSF) or granulocyte macrophagestimulating factor (GM-CSF) and pre-polarized during the 48 h with either IL-4 and IL-10 or IFN-γ and LPS, respectively (Fig. 1a)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with more than 890,000 new cases every year [1]. The consumption of alcohol and tobacco [3, 4] and an infection with the human papilloma virus (HPV) are strongly associated with HNSCC. The incidence of HPV-driven head and neck tumors is rapidly increasing [5, 6]. Patients with solid tumors receive RT in about 60% of the cases during the course of their disease [7]. It should be emphasized that ionizing radiation has a direct influence on the irradiated tumor cells, and has a broader systemic effect through the induction of immunogenic cell death, which has a modulating and stimulating effect on the immune system, leading in the ideal case to antitumoral immune responses [8,9,10,11,12,13,14]
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