PROJECT SUMMARY/ABSTRACT
Liposarcoma (LPS) is the most common type of soft tissue sarcoma. The most common subtypes are well-
differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma which are characterized by genomic
amplification of murine double minute 2 (MDM2), a negative regulator of p53, in over 90% of cases, while 7% of
human WD/DDLPS have a p53 mutation. Patients have a high risk of recurrence after surgical resection and
patients with metastatic disease have poor overall survival due to the poor response rates of the systemic
chemotherapy. While immunotherapy has shown tremendous efficacy in solid tumors, research focusing on the
immune biology of sarcoma has been slower than other tumor types. There is an urgent unmet need to
understand the liposarcoma tumor microenvironment (TME) to enable the discovery of new and efficacious
immunotherapeutic approaches for sarcoma patients. Memory T cells play crucial roles in anti-tumor immunity.
Resident memory T cells (TRM) which reside in tumors may be best suited to immunity against cancers growing
in tissues. Our group and others have demonstrated a favorable role of TRM in the TME with associated improved
patient survival across multiple tumor types. Characterization of memory T cells in LPS, and whether TRM are
present and functional, has not been explored. DDLPS patients who had improved progression-free survival in
a phase II trial of treatment with a PD1 inhibitor were found to have the presence of tertiary lymphoid structures
(TLS), an ectopic lymphoid structure that consists of T-cell and B-cell rich regions and other immune populations,
in their tumors. Since PD-1 inhibitors work by blocking this protein on T cells, it is imperative that we understand
how TRM interact within the TLS and TME. In order to mechanistically test this, an in vivo spontaneous
immunocompetent tumor model is necessary since cell-line derived tumors lack the complex tumor evolution
that occurs alongside immune responses. Genetically engineered mouse models (GEMMs) more dependably
mimic the human stoma and tumor microenvironment. Currently, there is no established spontaneous tumor
murine model for liposarcoma. Our first Aim is to validate an AAV8-Ap2.2-eGFP/Cre PTEN f/f p53 f/f C57BL/6
LPS GEMM model and characterize the intratumoral and systemic immune responses. The tumor and immune
characterization in this model will be compared to human data in order to establish the validity of using it as a
preclinical model. Our second Aim is to generate a Cre-inducible MDM2-overexpressing GEMM needed to
model the most common oncogenic drivers reported in human liposarcoma. The successful completion of this
project would highly impact the sarcoma community by providing a necessary model for use in preclinical studies
for the pursuit of novel and effective immunotherapeutics for patients.