Cytokine Profiling of Children, Adolescents, and Young Adults Newly Diagnosed with Sarcomas Demonstrates the Role of IL-1β in Osteosarcoma Metastasis

<b>Background:</b> Sarcomas are a heterogeneous group of mesenchymal tumors frequently diagnosed in pediatric and young adult patients. These tumors respond poorly to conventional immunotherapy, although the precise reason for this is not known. We sought to characterize the systemic immune response to sarcomas by measuring the levels of circulating cytokines in the plasma of newly diagnosed sarcoma patients, testing the hypothesis that the nature of a patient's immune response to their tumor directly affects outcome. <b>Methods:</b> Plasma was collected from newly diagnosed, treatment-naive pediatric sarcoma patients participating in an ongoing clinical trial, MCC20320. A panel of 18 cytokines was selected, and cytokine levels were measured using the Luminex platform. Cytokine levels were analyzed based on clinicopathological parameters such as gender, age, stage, and survival. <b>Results:</b> We found that the cytokine profile in patients newly diagnosed with sarcoma is distinct from healthy controls, but different sarcomas were not distinguishable. Patients with osteosarcoma who had elevated levels of multiple cytokines had inferior overall survival compared to those with fewer or no elevated levels. Similarly, elevated levels of individual cytokines and chemokines, including IL-24, CXCL5, and CXCL10, were associated with inferior event-free or overall survival in patients with osteosarcoma. Perhaps most significantly, elevated IL-1β at diagnosis was associated with metastatic presentation and inferior event-free survival in patients with osteosarcoma. <b>Conclusions:</b> These findings suggest that pediatric sarcoma patients mount a systemic immune response that may affect event-free or overall survival. IL-1β in particular may be a valuable therapeutic target for osteosarcoma patients.