Elucidating the role of MIF in the immunosuppressive tumor microenvironment of Ewing sarcoma
Ewing sarcoma is a malignant cancer of bone and soft tissues that affects children, adolescents and young adults. Currently, combinations of intensive chemotherapy, surgery and radiation are only 70% effective for children with a localized tumor. If the tumors have spread to distant sites, fewer than 1/3 will survive. Additionally, children who survive face a lifelong risk of adverse health effects due to toxicity of therapy, such as secondary cancers, infertility, and significant heart damage. New therapeutic advances are needed that are more effective with fewer toxic side-effects. For some pediatric cancers, recent progress has led to new treatments that use one’s own immune system to target cancer cells. However, immunotherapy has not been successful for Ewing sarcoma because we don’t understand how Ewing sarcoma tumor cells evade the immune system. Macrophage migration inhibitory factor (MIF) is a protein released by Ewing sarcoma and binds to immune cells like macrophages, helping the tumor escape immune detection. The role of MIF in Ewing sarcoma and how it affects the surrounding microenvironment is not known. Thus, understanding MIF is crucial for uncovering how Ewing sarcoma evades the immune system.
Project Goals
My project will focus on the role of Macrophage Migration Inhibitory Factor (MIF) in facilitating immune evasion in Ewing sarcoma. I have recently spatially localized the immune cells within the tumor microenvironment of Ewing sarcoma and identified one of the ways it communicates with macrophages, a key immune cell type. Using Ewing sarcoma tumors removed from pediatric patients during their cancer diagnosis and treatment, as well as a zebrafish genetic model of Ewing sarcoma developed at CHLA, I will apply newly-developed techniques to map the tumor microenvironment and examine tumor/macrophage interactions with and without MIF in living tissue and cells. Taking advantage of the transparency of zebrafish in early life stages, I will be able to visualize how immune cells change as tumors develop in the presence or absence of MIF. I will use the fish model to directly test MIF’s contribution to tumor growth, and evaluate potential therapeutic strategies targeting MIF. The long-term goal of this work is to identify MIF as a novel therapeutic target that can directly apply to patients in the future. My goal is not only to reduce treatment related toxicities for survivors of children with Ewing sarcoma but also to improve the treatment outcomes and responses for children with Ewing sarcoma in hopes to one day finding a cure.
