Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer

The increasing incidence of human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OSSC) demands development of novel therapies. Despite presenting at a more advanced stage, HPV(+) oropharyngeal squamous cell carcinoma (OSCC) have a better prognosis than their HPV(-) counterparts. We have previously demonstrated that clearance of HPV(+) OSCC during treatment with radiation and chemotherapy requires an immune response which is likely responsible for the improved clinical outcomes. To further elucidate the mechanism of immune-mediated clearance, we asked whether radiation therapy induces tumor cell changes that allow the body to recognize and aid in tumor clearance. Here, we describe a radiation-induced change in tumor surface protein expression that is critical for immune-mediated clearance. Radiation therapy decreases surface expression of CD47, a self-marker. CD47 is frequently overexpressed in head and neck squamous cell carcinoma and radiation induces a decrease of CD47 in a dose-dependent manner. We show that both in vitro and in vivo tumor cell CD47 protein levels are restored over time after sublethal radiation exposure and that protein levels on adjacent, normal tissues remain unaffected. Furthermore, reduction of tumor cell CD47 increases phagocytosis of these cells by dendritic cells and leads to increased interferon gamma and granzyme production from mixed lymphocytes. Finally, decreasing tumor cell CD47 in combination with standard radiation and chemotherapy results in improved immune-mediated tumor clearance in vivo. These findings help define an important mechanism of radiation-related immune clearance and suggest that decreasing CD47 specifically on tumor cells may be a good therapeutic target for HPV related disease. What's new? Oropharyngeal squamous cell carcinomas (OSCC) associated with human papilloma virus (HPV) infection have a better prognosis than their HPV- counterparts. This is in part explained by a strong immune response induced during radiation or chemotherapy treatment, the origin of which is largely unexplained. Vermeer and colleagues now report a novel mechanism how clearance of tumor cells can be enhanced. They describe a radiation-dependent decrease in surface CD47 levels in HPV+ tumors that augments immune cell activity in vitro, suggesting that CD47 aids in tumor immune evasion. They further show that a reduction of tumor CD47 levels results in decreased tumor volumes and improved survival in mice, pointing to the manipulation of CD47 as a novel immune-therapeutic strategy with implications beyond HPV+ OSCCs.