Characterization of a novel mouse model of undifferentiated pleomorphic sarcoma that is lymphocyte poor, macrophage rich, and resistant to immune checkpoint blockade

ABSTRACT: Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that disproportionately affect children and young adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, such approaches have proven ineffective for the majority of individuals with advanced sarcomas. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are needed in order to test and develop novel immunologically-based therapies for sarcoma. Herein we show that Cre- lox P-mediated simultaneous activation of Kras G12D , and deletion Trp53, in the hindlimb muscles of C57Bl/6 mice results in the development of highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS). The latter represents a model one of the most common human sarcoma subtypes both histologically and genetically. Furthermore, cell lines derived from the UPS tumors induced in C57Bl/6 mice can be transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both the spontaneous and transplanted UPS tumours demonstrates an immunologically- ‘quiescent’ microenvironment, characterized by a paucity of lymphocytes and spontaneous adaptive immune pathways in addition to dense macrophage infiltrates. UPS cell line induced tumours demonstrate mildly increased lymphocytic infiltrates as compared with the spontaneous UPS tumours, furthermore, growth of transplanted UPS was unaltered in lymphocyte deficient hosts. Despite expression of PD-1 on the tumour infiltrating lymphocytes, UPS tumours were resistant to immunological checkpoint blockade. This syngeneic transplantable UPS model that recapitulates many of the immunological features of human UPS will prove invaluable for the preclinical development and evaluation of novel immunotherapeutic approaches for targeting sarcomas.

ORGANISM(S): Mus musculus

PROVIDER: GSE174540 | GEO | 2021/06/24

REPOSITORIES: GEO