Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1 + Dendritic Cells

Cell Rep. 2019 Oct 1;29(1):162-175.e9. doi: 10.1016/j.celrep.2019.08.086.

Abstract

Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.

Keywords: CXCR3; PD-1; STING; XCR1; cancer immunotherapy; checkpoint blockade; cross-presentation; dendritic cells; induced pluripotent stem cells; type I interferon.

MeSH terms

  • Animals
  • Dendritic Cells / immunology*
  • Immunity / immunology*
  • Immunotherapy / methods
  • Induced Pluripotent Stem Cells / immunology*
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Type I / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Cells / immunology*
  • Neoplasms / immunology
  • Receptors, CXCR3 / immunology
  • Receptors, Chemokine / immunology*
  • Tumor Microenvironment / immunology

Substances

  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Receptors, CXCR3
  • Receptors, Chemokine
  • XC chemokine receptor 1, mouse