Acta Pharmaceutica Sinica B (May 2024)

Radiation-based immunogenic vaccine combined with a macrophage “checkpoint inhibitor” for boosting innate and adaptive immunity against metastatic colon cancers

  • Hongbo Xu,
  • Xianya Qin,
  • Yuanyuan Guo,
  • Siyu Zhao,
  • Xingxing Feng,
  • Runzan Zhang,
  • Tianyi Tian,
  • Li Kong,
  • Conglian Yang,
  • Zhiping Zhang

Journal volume & issue
Vol. 14, no. 5
pp. 2247 – 2262

Abstract

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Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors. Especially, X-ray- induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants. However, we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines, which can specifically bind with the MerTK receptor on macrophages, acting as a “checkpoint” to facilitate immune silence in the tumor microenvironment. Therefore, we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250, a macrophage MerTK “checkpoint inhibitor,” for treating peritoneal carcinomatosis in colon cancer. By incorporating UNC2250 into the treatment regimen, immunosuppressive efferocytosis of macrophages, which relies on MerTK-directed recognition of phosphatidylserine on vaccines, was effectively blocked. Consequently, the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages, thereby simultaneously eliciting robust adaptive and innate immunity. This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

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