Targeting CD47 and Angiogenesis Demonstrates Effective Anti-Tumor Effect in Bladder Cancer

Abstract

Background: Although immunotherapy has shown potential in cancer treatment, current immunotherapeutics for bladder cancer are limited by a low response rate. Therefore, it is necessary to investigate other suitable immunotherapeutic targets and strategies for bladder cancer. Methods: To evaluate whether CD47 could be a suitable target for bladder cancer immunotherapy, CD47 protein expression levels in 116 bladder cancer tissue samples were assessed by IHC staining. In vitro anti-tumor effect of blocking CD47 was examined by phagocytosis assays. In vivo anti-tumor effects of targeting CD47 and angiogenesis were experimented in the HSPCs-CDX model. Results: We find that CD47 is highly expressed in bladder cancer samples and is associated with poor prognosis. Blocking CD47 could enhance the human PBMC-derived macrophages’ phagocytosis of T24 (from 10.40% to 29.70%) and 5637 (from 5.31% to 33.52%) human bladder cancer cells, as well as demonstrate anti-tumor effects in the HSPCs-CDX model (tumor growth inhibition rate, TGI: 33.05%). During CD47 treatment, we observed that the level of angiogenesis increased after CD47 blockade, and it might undermine the effect of CD47 immunotherapy. We then combined CD47 blockade with anti-angiogenic drugs to treat bladder cancer and discovered that inhibiting angiogenesis could further improve the anti-tumor effect of CD47 blockade (TGI: 76.39%). Finally, we tested the anti-tumor effect of co-targeting CD47 and angiogenesis using a bispecific fusion protein, SIRPα-VEGFR1, which successfully inhibited tumor growth to a similar extent as a combination therapy. Conclusions: Our study suggests that targeting CD47 could inhibit the growth of bladder cancer by promoting macrophage-mediated anti-tumor immunity. Moreover, blocking CD47 and angiogenesis could achieve a potent anti-tumor effect and could be an effective immunotherapy strategy for bladder cancer.

Keywords

• bladder cancer
• CD47 blockade therapy
• innate immunity
• angiogenesis
• combinational therapy