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(+) OSCC’s 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 over-expressed in HNSCC and radiation induces a decrease of CD47 in a dose dependent manner. We show both in vitro and in vivo that tumor cell CD47 protein levels are restored over time following sub-lethal 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 IFNγ 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.

CD47 in the Tumor Microenvironment Limits Cooperation between Antitumor T-cell Immunity and Radiotherapy

“…Our previous studies and some others have observed that blocking CD47 alone does not result in significant tumor ablation (24), but combining CD47 blockade with radiation or specific cytotoxic antibodies enhances the anti-tumor activity (24, 46). On the other hand, we observed in our fibrosarcoma model in immunocompetent mice that blockade of CD47 alone moderately reduced tumor burden.…”

Chemoradiotherapy-Induced Upregulation of PD-1 Antagonizes Immunity to HPV-Related Oropharyngeal Cancer

“…Conversely, radiation and chemoradiation have been suggested to have an enhancing effect on the immune response to both HPV-negative (21) and HPV-positive (22) head and neck cancer. Intact host immunity has also proposed to be critical for efficacy of conventional radiation and chemoradiation therapy for HPVOPC (23,24) suggesting immune-dependent mechanisms of action. Such a beneficial role for (chemo)radiation in host immune response to HPVOPC would be consistent with recent clinical literature describing immune-stimulating effects of chemotherapy and radiation in melanoma (25,26) and esophageal squamous cell carcinoma (27).…”

Retrospective analysis of the impact of HPV status and smoking on mucositis in patients with oropharyngeal squamous cell carcinoma treated with concurrent chemotherapy and radiotherapy

“…Factors believed to be involved in a better response to treatment among HPV-positive patients (e.g., immune surveillance to viral-specific tumor antigens, an intact apoptotic response, absence of field cancerization), might facilitate an increased inflammatory response to chemotherapy and radiotherapy inside the tumor and in the surrounding mucosa, resulting in increased mucositis [12,23]. Because HPV-positive patients tend to be non-smokers (70% in our population), they lack mucosal alterations associated with long-term inflammatory insults from tobacco exposure.…”