Defining How Iron Metabolism and Cycling Shape the Immune Microenvironment in Synovial Sarcoma 2253974

Abstract

Abstract Introduction Synovial Sarcoma (SyS) is an aggressive soft tissue sarcoma that is unresponsive to immune checkpoint blockades or adoptive cell therapy, leaving few treatment options. The disease originates in the synovial lining of the joint space and disproportionately affects young adults between the ages of 20 and 30. Resistance to immunotherapies is due to its genetic stability and low tumor mutational burden; as a result, the current standard of care is limited to wide surgical excision and chemotherapy. To improve the efficacy of immunotherapies against SyS, we aim to elucidate how the dysregulation of iron metabolism and cycling in leukocytes drive tumor growth while simultaneously creating an immunosuppressive tumor microenvironment. Methods Utilizing single-cell RNA sequencing, we characterized the immune microenvironment in human monophasic and biphasic SyS tumors from 12 different patients. Results Preliminary data show that biphasic SyS is immunologically distinct from monophasic SyS, both functionally and compositionally. Analysis of iron metabolism and cycling within leukocytes illustrates high levels of iron storage with low levels of iron metabolism, indicating potential malfunction of metabolic pathways, including the electron transport chain. This malfunction may lead to attenuated anti-tumor responses from tumor-infiltrating leukocytes and unchecked tumor growth. Conclusion Our findings elucidate potential immunotherapeutic strategies that target iron uptake in tumor-infiltrating leukocytes, such as a CD163-blocking antibody, to alleviate their immunosuppressive phenotype and promote an anti-tumor response. This research aims to improve and expand current treatment options for patients with synovial sarcoma. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)