| Popis: |
Immunotherapies have been largely ineffective for pediatric soft tissue sarcomas, in particular for fusion-positive rhabdomyosarcoma (FP-RMS), characterized by the PAX-FOXO1 gene fusion. We are hampered by a paucity of predictive, immune-competent mouse models of this cancer with which to develop novel and effective immune-based therapies. To overcome this barrier, we analyzed the immune microenvironment of one of the few genetically-engineered mouse models (GEMM) of FP-RMS. Briefly, this model is driven by conditional knock-in expression of Pax3:Foxo1 at the endogenous Pax3 locus, with or without conditional loss of MST1/2 (gene name Stk4/3), a Hippo pathway mediator that is modulated by PAX3-FOXO1. These two genotypes demonstrate different disease penetrance and tumor location, with mice bearing loss of MST1/2 exhibiting higher tumor penetrance and favoring head and neck disease sites. We hypothesize that these models exhibit differences in tumor-immune interactions in the microenvironment that correlate with these phenotypic differences. We aim to characterize the immune microenvironment differences between these tumors and to establish this GEMM as a predictive, syngeneic model of FP-RMS. Tumors were generated spontaneously from a GEMM of FP-RMS. Tumors expressed PAX3-FOXO1 and either carried a conditional loss of MST1/2 (MSTnull) or native MST1/2 (MSTwt). We analyzed 8 formalin-fixed, paraffin-embedded (FFPE) tumors and 2 tumor-derived cell lines from these novel models. FFPE tumor samples were analyzed via immunohistochemistry (IHC) for CD3 (T cell marker) and CD11b (myeloid cell marker) and were scored for immune cell infiltration. Overall, tumors demonstrate poor CD3+ T cell infiltration with significantly higher infiltration of CD11b+ myeloid cells (p=0.0002); this trend is also seen within the individual MSTwt (p=0.0286) and MSTnull cohorts (p=0.0286). There was no significant difference in CD3+ T cell or CD11b+ myeloid cell density between the two genotypes. The drivers of this immune phenotype and the role of Hippo pathway signaling in mediating RMS tumor immune cell infiltration warrants further investigation. Additional ongoing studies are utilizing a spatial gene expression platform to visualize the spatially-preserved transcriptome of intact tumors to reveal potential pathways mediating the immune microenvironment. Citation Format: Erin E. Resch, Kristianne M. Oristian, Elizabeth Mendes, Corinne M. Linardic, Brian H. Ladle. Interrogating the immune microenvironment of a novel mouse model of fusion positive rhabdomyosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3534. |
