In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 7 ( 2021-7-9), p. e0253864-
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 Kras G12D , 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0253864
DOI:
10.1371/journal.pone.0253864.g001
DOI:
10.1371/journal.pone.0253864.g002
DOI:
10.1371/journal.pone.0253864.g003
DOI:
10.1371/journal.pone.0253864.g004
DOI:
10.1371/journal.pone.0253864.g005
DOI:
10.1371/journal.pone.0253864.s001
DOI:
10.1371/journal.pone.0253864.s002
DOI:
10.1371/journal.pone.0253864.s003
DOI:
10.1371/journal.pone.0253864.s004
DOI:
10.1371/journal.pone.0253864.s005
DOI:
10.1371/journal.pone.0253864.r001
DOI:
10.1371/journal.pone.0253864.r002
DOI:
10.1371/journal.pone.0253864.r003
DOI:
10.1371/journal.pone.0253864.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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