Soft tissue sarcoma (STS) is a rare but heterogeneous collection of fatal malignancies that arise from mesenchymal tissues. Metastatic STS exhibits a 5-year survival rate of less than 15%, highlighting the need for improved therapies. Although the clinical success of immunotherapies such as immune checkpoint blockade demonstrates the importance of the immune system in the control of cancer, the majority of patients fail to respond to these therapies, underscoring the need to elucidate additional immune evasion mechanisms in solid tumors. It is now known that the abundance of immunosuppressive myeloid cells such as tumor associated macrophages (TAMs), and conversely, the paucity of immunostimulatory myeloid cells such as dendritic cells (DCs), pose major barriers to successful anti-tumor immunity. This proposal builds upon unpublished preliminary data demonstrating that high levels of retinoic acid in the tumor microenvironment (TME) may be an important immune evasion mechanism utilized by sarcoma. Specifically, retinoic acid may prevent the intratumoral differentiation of monocytes into DCs. Using sarcoma mouse models, Aim 1.1 explores the molecular mechanism of retinoic acid's influence on intratumoral monocyte differentiation, and Aim 1.2 explores the cellular mechanism by which retinoic acid inhibits anti-tumor immunity. As an independent aim, Aim 2 explores the regulation of retinoic acid production within the TME. Based on unpublished preliminary data demonstrating that Th2 cytokines strongly induce sarcoma cells to produce retinoic acid, Aim 2.1 explores whether IL-13 signaling regulates retinoic acid production in vivo, and Aim 2.2 seeks to determine the cellular source of IL-13 in sarcoma. Together, this work will elucidate a novel immune evasion axis in solid tumors and may lead to the development of improved sarcoma immunotherapies. This project will be co-sponsored by two dedicated mentors with complementary expertise in immunology and cancer biology. Together, they have assembled a comprehensive training plan that will be instrumental in the applicant's development into a successful, independent academic investigator.
Soft tissue sarcoma (STS) is an understudied lethal disease with inadequate treatment options. We have discovered that retinoic acid is a potent immunosuppressive metabolite in the sarcoma microenvironment. This proposal explores the effects of retinoic acid on antigen presenting cells in sarcoma and may uncover a novel immune evasion axis that will serve as a basis for improved sarcoma immunotherapy.
