Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH4-induces immunostimulatory-shift of breast cancer

Biochem Pharmacol. 2020 Jun:176:113887. doi: 10.1016/j.bcp.2020.113887. Epub 2020 Feb 27.

Abstract

Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immuno-suppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH4)-the nitric oxide synthase (NOS) cofactor-redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells.

Keywords: Arginine metabolism; Breast cancer; Macrophage reprogramming; Nitric oxide; Tumor-associated macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arginine / metabolism*
  • B7-H1 Antigen / metabolism
  • Biopterins / analogs & derivatives
  • Biopterins / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Macrophages / classification
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Polyamines / metabolism*
  • Pterins / metabolism
  • Pterins / pharmacology*
  • STAT3 Transcription Factor / metabolism
  • THP-1 Cells

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Polyamines
  • Pterins
  • STAT3 Transcription Factor
  • Biopterins
  • Nitric Oxide
  • Arginine
  • sepiapterin
  • Nitric Oxide Synthase
  • sapropterin