Regulation of host immune response in osteosarcoma

Osteosarcoma (OS) is the most common primary bone malignancy, accounting for ~2% of childhood cancers. The relative 5-year survival rate for patients <30 years is ~60%, for patients with metastatic OS the rate drops to <20% - rates that have not changed over the last three decades. There is a critical need to develop novel therapeutic strategies for OS. Immunotherapy is dramatically changing how we treat patients with cancer, however, it is only effective when immune cells are actively recognize and fight the cancer. Our previous work provided evidence that OS tumors show differing levels of immune cell infiltration, and that low levels of immune cell gene expression are strongly associated with metastasis and poor patient survival. We have identified a set of microRNAs whose expression also correlates with poor survival. Our central hypothesis is that lack of a robust immune response and disruption of miRNA-mediated signaling networks are two key factors contributing to OS progression, response to therapy, and patient survival outcomes. We have mRNA and microRNA sequence data for 55 human OS tumors, 20 of which will be further tested using histochemistry to reveal which tumors have active immune cell infiltration. This project will validate our novel expression-based method for identifying patients who have an active anti-tumor immune response, and are thus most likely to benefit from adjuvant immunotherapy. Our integrated expression analysis should validate novel therapeutic targets and advance our understanding of OS pathobiology, particularly the molecular mechanisms used by tumors to suppress the host immune system. These results are expected to have a positive translational impact as this knowledge will aid in the identification of novel therapeutic targets and inform future treatment and detection strategies, thereby improving the overall survival of osteosarcoma patients.