Comparative Immunology and Immunotherapy of Canine Osteosarcoma

Approximately 800 people are diagnosed with osteosarcoma (OSA) per year in the USA. Although 70% of patients with localized OSA are cured with multiagent chemotherapy and surgical resection, the prognosis for patients with metastatic or relapsed disease is guarded. The small number of patients diagnosed annually contributes to an incomplete understanding of disease pathogenesis, and challenges in performing appropriately powered clinical trials and detecting correlative biomarkers of response. While mouse models of OSA are becoming increasingly sophisticated, they generally fail to accurately recapitulate tumor heterogeneity, tumor microenvironment (TME), systemic immune dysfunction, and the clinical features of tumor recurrence, metastases, and chemoresistance, which influence outcome. Pet dogs spontaneously develop OSA with an incidence that is 30-50 times higher than humans. Canine OSA parallels the human disease in its clinical presentation, biological behavior, genetic complexity, and therapeutic management. However, despite therapy, most dogs die from metastatic disease within 1 year of diagnosis. Since OSA occurs in immune-competent dogs, immune factors that sculpt tumor immunogenicity and influence responses to immune modulation are in effect. In both species, immune modulation has shown beneficial effects on patient outcome and work is now underway to identify the most effective immunotherapies, combination of immunotherapies, and correlative biomarkers that will further improve clinical response. In this chapter, the immune landscape of canine OSA and the immunotherapeutic strategies used to modulate antitumor immunity in dogs with the disease will be reviewed. From this immunological viewpoint, the value of employing dogs with spontaneous OSA to accelerate and inform the translation of immunotherapies into the human clinic will be underscored.