CD47 blockade enhances the efficacy of intratumoral STING-targeting therapy by activating phagocytes
Akemi Kosaka, Kei Ishibashi, Toshihiro Nagato, Hidemitsu Kitamura, Yukio Fujiwara, Syunsuke Yasuda, Marino Nagata, Shohei Harabuchi, Ryusuke Hayashi, Yuki Yajima, Kenzo Ohara, Takumi Kumai, Naoko Aoki, Yoshihiro Komohara, Kensuke Oikawa, Yasuaki Harabuchi, Masahiro Kitada, Hiroya Kobayashi, Takayuki Ohkuri
Abstract
Activation of STING signaling plays an important role in anti-tumor immunity, and we previously reported the anti-tumor effects of STING through accumulation of M1-like macrophages in tumor tissue treated with a STING agonist. However, myeloid cells express SIRPα, an inhibitory receptor for phagocytosis, and its receptor, CD47, is overexpressed in various cancer types. Based on our findings that breast cancer patients with highly expressed CD47 have poor survival, we evaluated the therapeutic efficacy and underlying mechanisms of combination therapy with the STING ligand cGAMP and an antagonistic anti-CD47 mAb using E0771 mouse breast cancer cells. Anti-CD47 mAb monotherapy did not suppress tumor growth in our setting, whereas cGAMP and anti-CD47 mAb combination therapy inhibited tumor growth. The combination therapy enhanced phagocytosis of tumor cells and induced systemic anti-tumor immune responses, which rely on STING and type I IFN signaling. Taken together, our findings indicate that coadministration of cGAMP and an antagonistic anti-CD47 mAb may be promising for effective cancer immunotherapy.