Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours

Nat Biomed Eng. 2020 May;4(5):531-543. doi: 10.1038/s41551-020-0549-2. Epub 2020 Apr 13.


Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in 'immunologically cold' tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD-IL-12) in mice bearing aggressive mouse tumours, CBD-IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD-IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD-IL-12 potently synergized with CPI to eradicate large established melanomas, induced antigen-specific immunological memory and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD-IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Collagen / metabolism*
  • Disease Models, Animal
  • Epitopes / immunology
  • Female
  • Immunity, Innate / drug effects
  • Inflammation / pathology*
  • Interleukin-12 / pharmacology
  • Interleukin-12 / therapeutic use*
  • Melanoma / drug therapy
  • Melanoma / pathology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neoplasms / drug therapy*
  • Neoplasms / immunology*
  • Protein Binding / drug effects
  • Protein Domains
  • Remission Induction
  • Tumor Burden / drug effects
  • Tumor Microenvironment / drug effects


  • Epitopes
  • Interleukin-12
  • Collagen

Associated data

  • figshare/10.6084/m9.figshare.11971371