The KrasG12D;Trp53fl/fl murine model of undifferentiated pleomorphic sarcoma is macrophage dense, lymphocyte poor, and resistant to immune checkpoint blockade

PLoS One. 2021 Jul 9;16(7):e0253864. doi: 10.1371/journal.pone.0253864. eCollection 2021.

Abstract

Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that affect children and adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, these therapeutic strategies have been minimally effective in sarcoma so far. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are essential to advance sarcoma immunology research. Herein we show that Cre-mediated activation of KrasG12D, and deletion of Trp53, in the hindlimb muscles of C57Bl/6 mice results in the highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS), one of the most common human sarcoma subtypes. Cell lines derived from spontaneous UPS tumours can be reproducibly transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both spontaneous and transplanted UPS tumours demonstrates an immunologically-'quiescent' microenvironment, characterized by a paucity of lymphocytes, limited spontaneous adaptive immune pathways, and dense macrophage infiltrates. Macrophages are the dominant immune population in both spontaneous and transplanted UPS tumours, although compared to spontaneous tumours, transplanted tumours demonstrate increased spontaneous lymphocytic infiltrates. The growth of transplanted UPS tumours is unaffected by host lymphocyte deficiency, and despite strong expression of PD-1 on tumour infiltrating lymphocytes, tumours are resistant to immunological checkpoint blockade. This spontaneous and transplantable immune competent UPS model will be an important experimental tool in the pre-clinical development and evaluation of novel immunotherapeutic approaches for immunologically cold soft tissue sarcomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Hindlimb
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Immune Checkpoint Inhibitors / therapeutic use
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Muscle Neoplasms / genetics*
  • Muscle Neoplasms / immunology
  • Muscle Neoplasms / pathology
  • Muscle, Skeletal / pathology
  • Mutation
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Sarcoma / genetics*
  • Sarcoma / immunology
  • Sarcoma / pathology
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Immune Checkpoint Inhibitors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was supported by funding from the Alberta Cancer Foundation, Alberta Children's Hospital Foundation, and the Cancer Research Society, all to MJM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.