Abstract B38: Single-cell RNA-seq analysis of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity

Abstract

Abstract Soft-tissue sarcomas (STS) are mesenchymal tumors that affect almost 200,000 individuals worldwide each year. Surgery is the standard treatment, followed by anthracycline-based chemotherapy, either alone or in combination with ifosfamide. Still, the 5-year survival rate is below 20% for advanced and metastatic STS. A main clinical challenge is creating and implementing therapies that can successfully treat the primary tumors so that the disease burden is eradicated, and relapsing lesions are prevented. Immunotherapy approaches such as anti-PD1/PDL1 have produced only marginal results for sarcoma patients. Novel investigations in this respect are hindered by the lack of knowledge of the sarcoma immune microenvironment and the scarcity of STS immune-competent mouse models. We therefore developed a mouse model of undifferentiated pleiomorphic sarcoma (UPS), one of the most aggressive STS subtypes, and employed single-cell RNA-sequencing to characterize the immune composition of the UPS mass. scRNA-seq showed that macrophages, the main immune cells in sarcoma, exhibit distinct activation states, ranging from anti-tumorigenic to pro-tumorigenic. Notably, sarcoma cells used the pleiotropic cytokine Macrophage Migration Inhibitory Factor (MIF) to interact with macrophages expressing the CD74 receptor, to switch macrophages’ activation state and pro-tumorigenic potential. Blocking the expression of MIF in sarcoma cells favored the accumulation of macrophages with inflammatory and antigen-presenting profiles, hence reducing tumor growth. These data pave the way for testing new therapies aimed at re-shaping the sarcoma microenvironment, in combination with the standard of care. Citation Format: Jlenia Guarnerio. Single-cell RNA-seq analysis of a soft-tissue sarcoma model reveals the critical role of tumor-expressed MIF in shaping macrophage heterogeneity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B38.