title: Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer.
abstract: 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.
authors.affiliation: Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57104, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.forename: William C
authors.initials: WC
authors.lastname: Spanos
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
authors.forename: Annie M
authors.initials: AM
authors.lastname: Bruns
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Lee
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051928:CD47 Antigen / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000532:radiotherapy* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000627:therapeutic use; D004307:Dose-Response Relationship, Radiation; D053804:Granzymes / Q000276:immunology; D052162:Human papillomavirus 16 / Q000302:isolation & purification; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D051379:Mice; D009959:Oropharyngeal Neoplasms / Q000276:immunology* / Q000532:radiotherapy* / Q000821:virology; D030361:Papillomavirus Infections / Q000150:complications*; D010587:Phagocytosis; D018714:Radiotherapy, Adjuvant
chemical_list: D000970:Antineoplastic Agents; D051928:CD47 Antigen; C497894:CD47 protein, human; C497895:Cd47 protein, mouse; D007371:Interferon-gamma; D053804:Granzymes; D002945:Cisplatin