TYRO3 induces anti-PD-1/PD-L1 therapy resistance by limiting innate immunity and tumoral ferroptosis

J Clin Invest. 2021 Apr 15;131(8):e139434. doi: 10.1172/JCI139434.

Abstract

Immune checkpoint blockade therapy has demonstrated promising clinical outcomes for multiple cancer types. However, the emergence of resistance as well as inadequate biomarkers for patient stratification have largely limited the clinical benefits. Here, we showed that tumors with high TYRO3 expression exhibited anti-programmed cell death protein 1/programmed death ligand 1 (anti-PD-1/PD-L1) resistance in a syngeneic mouse model and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, TYRO3 inhibited tumor cell ferroptosis triggered by anti-PD-1/PD-L1 and facilitated the development of a protumor microenvironment by reducing the M1/M2 macrophage ratio, resulting in resistance to anti-PD-1/PD-L1 therapy. Inhibition of TYRO3 promoted tumor ferroptosis and sensitized resistant tumors to anti-PD-1 therapy. Collectively, our findings suggest that TYRO3 could serve as a predictive biomarker for patient selection and a promising therapeutic target to overcome anti-PD-1/PD-L1 resistance.

Keywords: Cancer; Cancer immunotherapy; Cell Biology; Immunotherapy; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Resistance, Neoplasm / immunology*
  • Ferroptosis / drug effects
  • Ferroptosis / genetics
  • Ferroptosis / immunology*
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Immunity, Innate*
  • Mice
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / immunology*
  • THP-1 Cells

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • Cd274 protein, mouse
  • Immune Checkpoint Inhibitors
  • Neoplasm Proteins
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptor Protein-Tyrosine Kinases
  • TYRO3 protein, human
  • Tyro3 protein, mouse