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Preclinical Models & Translational Research

(P 246) IMMUNOCOMPETENT MODELING OF PLEOMORPHIC LIPOSARCOMA

Location: The Liffey, Level 1
Objective:

Introduction: Soft-tissue sarcoma represents an uncommon and heterogenous group of tumors of mesenchymal origin that carries a mortality burden incommensurate with its prevalence. Local treatment largely consists of radiation therapy and wide surgical resection, but options for systemic therapy in the setting of metastatic disease are limited and largely ineffective, prompting exploration of novel therapeutic strategies and experimental models. As with other cancers, sarcoma cell lines and patient-derived xenograft models have been developed and used to characterize these tumors and identify therapeutic targets, but these models have inherent limitations. The establishment of genetically-engineered mouse models represents a more realistic framework for reproducing sarcoma pathologic and therapeutic conditions.
Pleomorphic liposarcoma is a rare sub-group of soft-tissue sarcoma with complex genomic features, frequently involving Tp53 and Rb1 mutations.

Methods:

Methods: Tp53fl/fl/Rb1fl/fl/ Ptenfl/fl (RPP) mice were used to reliably generate an immunocompetent model of mouse pleomorphic liposarcoma through Cre-mediated conditional silencing of the Tp53, Rb1, and Pten tumor suppressor genes. Evaluation of tumor-infiltrating lymphocytes was assessed with immunostaining for CD4, CD8, and PD-L1, and flow cytometry with analysis of CD45, CD3, CD4, CD8, CD19, F4/80, CD11b, and NKp46 sub-populations.

Results:

Results: Mice reliably produced noticeable soft-tissue tumors in approximately 12 weeks with rapid tumor growth between 12 and 20 weeks of life, after which mice reached euthanasia criteria. Histologic features were consistent with pleomorphic liposarcoma, including widespread pleomorphic lipoblasts. Immunostaining and flow cytometry demonstrated scant tumor infiltrating lymphocytes.

Conclusion:

Conclusion: A genetically engineered RPP mice reliably produced soft-tissue tumors consistent with pleomorphic liposarcoma, which immunological findings consist with other soft-tissue sarcomas. This model may demonstrate utility in testing treatments for this rare disease, including immunomodulatory therapies.