Investigating the role of PSAT1 in tumor-associated macrophages for sarcoma immunotherapy
Dr. Stanley Huang – Case Western Reserve University - School of Medicine, Cleveland, OH
Sarcomas are a heterogeneous group of soft-tissue and bone tumors affecting both children and adults. However, the backbone of sarcoma therapy has not been changed for decades, and improvement in survival outcomes has come to a standstill1. Although recent clinical outcomes of immune-checkpoint blockade therapies have been promising, sarcomas clinical trials have demonstrated minimal response. In the tumor microenvironment (TME), tumor-associated macrophages (TAMs) represent one of the most abundant immune cells and are characterized by heterogeneous and plastic features, giving rise to populations spanning from antitumorigenic towards pro-tumorigenic TAMs2. Studies have established that TAMs directly facilitate cancer development and metastasis in patients3,4; and, importantly, it has been reported that immunosuppressive milieu of sarcoma is dominated and sustained by TAMs5. It is known that changes in metabolism are intrinsic to, and pivotal for, macrophage immunity6. We have found that the TME evoked activation of PSAT1-mediated serine metabolism promoting immunosuppression of TAMs. Ablation of PSAT1 signaling strongly impeded protumorigenic phenotypes and inhibited essential cellular metabolic programs in TAMs. In this proposal, we will investigate the role of PSAT1 metabolic signaling in TAMs, and metabolically intervene TAMs to alleviate the immunosuppressive properties, thus enhancing the anti-tumor immune response in sarcomas.
