Exploring the role of CSPG4 in chemotherapy resistance and assessing its potential as a target for immune-based therapies for the management of osteosarcoma

Osteosarcoma (OSA), a rare and aggressive bone tumor affecting children and adolescents, poses significant challenges in oncology. Limited treatment options (surgery and chemotherapy), result in a poor prognosis, with a 5-year survival rate below 20% for metastatic cases. However, treatment failure is frequent, mainly attributed to the development of resistance mechanisms, in a context of a “cold” tumor microenvironment. Immunotherapy has emerged as an alternative avenue and in this panorama, identifying relevant targets offers potential for triggering an effective anti-tumor immune response, which could work synergistically with chemotherapy and revolutionize OSA treatment. One promising target is the chondroitin sulfate proteoglycan (CSPG)4, widely studied in several tumors, being overexpressed in both differentiated tumor cells and cancer stem cells, where it is associated with the malignant behavior, including chemotherapy resistance, while barely expressed in normal tissues. Recently, it has been shown to play a key role in OSA biology. CSPG4 immune-targeting using a chimeric human/dog-CSPG4 DNA vaccine has shown immunogenicity and anti-tumor potential in comparative OSA models including human surrogate mouse models and client-owned OSA-affected dogs. To advance the understanding and treatment of OSA, this study aims to characterize the role of CSPG4 in chemoresistance and explore potential synergies between anti-CSPG4 vaccination and chemotherapy, both in vitro and in vivo. Results from mouse, canine and human models are integrated to investigate the potential mechanisms of action of combinatorial approaches and to validate the translational potential of proposing CSPG4 immune-targeting plus chemotherapy, for improving the clinical management of OSA-affected (canine and human) patients.