Blockade of CD47 Increases Cell and Tissue Survival After Radiation Injury Trough the Inhibition of Cell Death and Activation of Autophagy

Over half of all cancer patients will require radiation therapy for the clinical management of their disease however achieving a curative response is limited by off-target toxicities to normal cells. CD47 is a receptor for the secreted protein thrombospondin-1 (TSP-1). Our laboratory has reported that blockade of the TSP-1 and its receptor CD47 results in the profound radioprotection of soft tissues and bone marrow with doses of ionizing radiation (IR) used for radiotherapy of cancer. Suppression of CD47 in combination with IR enhances the radiation-induced delay in a syngeneic melanoma mouse model reducing tumor volume by 40% when compared to tumors of control animals. Moreover blockade of CD47 also increased survival of mice exposed to total body irradiation by 80% when compared to 50% in WT mice. Our data indicates that the observed effects may be mediated induction of autophagy genes. Autophagy is a mechanism activated in eukaryotic cells in response to metabolic and other types of stress allowing cell survival. Our experiments demonstrate that irradiated tissues from mice and cultured cells lacking CD47 have significant increases in Beclin-1 and ATG-5. We also observe p62/sequestosome protein degradation and increased autophagosome formation measured by immunofluorescent LC3 antibody in cultured T cells lacking CD47.   Suppression of CD47 in cancer cells does not increase radio-resistance and does not increase autophagy after IR. The selective activation of autophagy to protect cells in the tumor microenvironment is a novel paradigm that may explain the tumor ablation observed in our in vivo animal models.