Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Cell. 2021 Apr 15;184(8):2033-2052.e21. doi: 10.1016/j.cell.2021.02.048. Epub 2021 Mar 24.

Abstract

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.

Keywords: T cells; cancer immunology; genetically engineered myeloid cells; immune suppression; immunotherapy; interleukin 12; metastasis tumor microenvironment; pre-metastatic niche; stem cell niche.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adaptive Immunity
  • Animals
  • Cell Line, Tumor
  • Genetic Engineering
  • Humans
  • Immunosuppression Therapy*
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism
  • Lung / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / mortality
  • Lung Neoplasms / pathology
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / cytology
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism*
  • Neoplasm Metastasis
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Survival Rate
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • Tumor Microenvironment

Substances

  • Interleukin-12