Blockade of IL-10 Signaling Ensures Mifamurtide Efficacy in Metastatic Osteosarcoma

SIMPLE SUMMARY: Osteosarcoma is a highly aggressive and metastasizing primary bone neoplasm with poor patient survival rates. Mifamurtide is an immunostimulant drug whose clinical efficacy is still debated. Here we identified IL-10 as a new possible target useful to improve mifamurtide effectiveness on metastatic OS. Indeed, we demonstrated that in patients, high levels of IL-10 correlate with mortality. Moreover, the use of anti-IL-10 antibodies causes a significantly increased mortality rate in highest-grade OS cells and lower formation of lung metastases in an in vivo mouse model. These data suggest a possible clinical application of anti-IL-10 antibody and mifamurtide combined treatment as an effective approach for the treatment of metastatic osteosarcomas. ABSTRACT: Osteosarcoma (OS) is the most common primary malignancy of the bone, highly aggressive and metastasizing, and it mainly affects children and adolescents. The current standard of care for OS is a combination of surgery and chemotherapy. However, these treatment options are not always successful, especially in cases of metastatic or recurrent osteosarcomas. For this reason, research into new therapeutic strategies is currently underway, and immunotherapies have received considerable attention. Mifamurtide stands out among the most studied immunostimulant drugs; nevertheless, there are very conflicting opinions on its therapeutic efficacy. Here, we aimed to investigate mifamurtide efficacy through in vitro and in vivo experiments. Our results led us to identify a new possible target useful to improve mifamurtide effectiveness on metastatic OS: the cytokine interleukin-10 (IL-10). We provide experimental evidence that the synergic use of an anti-IL-10 antibody in combination with mifamurtide causes a significantly increased mortality rate in highest-grade OS cells and lower metastasis in an in vivo model compared with mifamurtide alone. Overall, our data suggest that mifamurtide in combination with an anti-IL-10 antibody could be proposed as a new treatment protocol to be studied to improve the outcomes of OS patients.