Inhibition of vascular adhesion protein-1 enhances the anti-tumor effects of immune checkpoint inhibitors

Tomonari Kinoshita, Mohammad Abu Sayem, Tomonori Yaguchi, Budiman Kharma, Kenji Morii, Daiki Kato, Shigeki Ohta, Yukihiko Mashima, Hisao Asamura, Yutaka Kawakami

Research output: Contribution to journalArticlepeer-review

Abstract

Modulation of the immunosuppressive tumor microenvironment (TME) is essential for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Adhesion molecules and enzymes such as vascular adhesion protein-1 (VAP-1), which are expressed in some cancers and tumor vascular endothelial cells, may be involved in the generation of an immunosuppressive TME. In this study, the role of VAP-1 in TME was investigated in 2 murine colon cancer models and human cancer cells. Intraperitoneal administration of the VAP-1-specific inhibitor U-V296 inhibited murine tumor growth by enhancing IFN-γ-producing tumor antigen-specific CD8+ T cells. U-V296 exhibited significant synergistic anti-tumor effects with ICIs. In the TME of mice treated with U-V296, the expression of genes associated with M2-like macrophages, Th2 cells (Il4, Retnla, and Irf4), angiogenesis (Pecam1), and fibrosis (Acta2, Loxl2) were significantly decreased, and the Th1/Th2 balance was increased. H2O2, an enzymatic product of VAP-1, which promoted the production of IL-4 by mouse Th2 and inhibited IFN-γ by mouse Th1 and human tumor-infiltrating lymphocytes, was decreased in tumors and CD31+ tumor vascular endothelial cells in the TMEs of mice treated with VAP-1 inhibitor. TCGA database analysis showed that VAP-1 expression was a negative prognostic factor in human cancers, exhibiting a significant positive correlation with IL-4, IL4R, and IL-13 expression and a negative correlation with IFN-γ expression. These results indicated that VAP-1 is involved in the immunosuppressive TMEs through H2O2-associated Th2/M2 conditions and may be an attractive target for the development of combination cancer immunotherapy with ICIs.

Original languageEnglish
Pages (from-to)1390-1401
Number of pages12
JournalCancer science
Volume112
Issue number4
DOIs
Publication statusPublished - 2021 Apr

Keywords

  • CTLs
  • HO
  • ICIs
  • VAP-1 inhibitor
  • immunosuppression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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