Myeloid Cells in the Immunosuppressive Microenvironment as Immunotargets in Osteosarcoma

Cyrus J Sholevar,1 Natalie M Liu,1 Tasneem Mukarrama,2 Jinhwan Kim,2 Jessica Lawrence,3 Robert J Canter1 1Department of Surgery, Division of Surgical Oncology, University of California Davis, Sacramento, CA, USA; 2Biomedical Engineering, University of California Davis, Sacramento, CA, USA; 3Department of Surgical & Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA, USACorrespondence: Robert J Canter, Research Building III, University of California Davis, 4645 Second Ave Room 2200D, Sacramento, CA, 95817, USA, Email [email protected]: Osteosarcoma is an aggressive primary malignant bone tumor associated with high rates of metastasis and poor 5-year survival rates with limited improvements in approximately 40 years. Standard multimodality treatment includes chemotherapy and surgery, and survival rates have remained stagnant. Overall, response rates to immunotherapy like immune checkpoint inhibitors have been disappointing in osteosarcoma despite exciting results in other epithelial tumor types. The poor response of osteosarcoma to current immunotherapies is multifactorial, but a key observation is that the tumor microenvironment in osteosarcoma is profoundly immunosuppressive, and increasing evidence suggests a significant role of suppressive myeloid cells in tumor progression and immune evasion, particularly by myeloid-derived suppressor cells. Targeting suppressive myeloid cells via novel agents are attractive strategies to develop novel immunotherapies for osteosarcoma, and combination strategies will likely be important for durable responses. In this review, we will examine mechanisms of the immunosuppressive microenvironment, highlight pre-clinical and clinical data of combination strategies including colony-stimulating factor 1 (CSF-1) receptor, phosphoinositide 3-kinase (PI3K), CXCR4, and checkpoint inhibition, as well as the role of canine models in elucidating myeloid cells as targets in osteosarcoma immunotherapy.Keywords: MDSC, macrophage, immunotherapy, sarcoma, tumor microenvironment