Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Cell. 2020 Oct 29;183(3):771-785.e12. doi: 10.1016/j.cell.2020.09.058.

Abstract

Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.

Keywords: cancer immunotherapy; granulopoiesis; inflammation; innate immune memory; interferon; neutrophils; trained immunity; β-glucan.

Publication types

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

MeSH terms

  • Adaptive Immunity
  • Adoptive Transfer
  • Animals
  • Epigenesis, Genetic
  • Granulocytes / immunology*
  • Immunity, Innate*
  • Interferon Type I / metabolism
  • Mice, Inbred C57BL
  • Monocytes / metabolism
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neutrophils / metabolism
  • Phenotype
  • Receptor, Interferon alpha-beta / deficiency
  • Receptor, Interferon alpha-beta / metabolism
  • Transcription, Genetic
  • Transcriptome / genetics
  • beta-Glucans / metabolism

Substances

  • Ifnar1 protein, mouse
  • Interferon Type I
  • beta-Glucans
  • Receptor, Interferon alpha-beta