Uncover principles underlying cryoablation-induced immunotherapy effects in sarcomas

Malignant sarcomas comprise 12% of all pediatric cancers. Despite its rare occurrence, sarcomas are life threatening and difficult to treat, and nearly half of all patients will have recurrence and metastasis.  The two most prevalent sarcomas in the pediatric and adolescent population are Osteosarcoma and Rhabdomyosarcoma (RMS). Osteosarcoma (OS) is the most prevalent malignant bone cancer with a high propensity for lung metastasis in children and adolescent and young adults (AYA), with ~400-600 cases a year in the United States. Despite aggressive chemotherapy and surgery, the outcome for unresectable pulmonary metastatic or recurrent/refractory OS remains poor over the past 4 decades. On the other hand, Rhabdomyosarcoma (RMS) is the most common soft tissue tumor in childhood, accounting for ~300-400 cases or ~3% of all childhood cancers each year. The mainstay of RMS therapy has remained largely unchanged, consisting of surgery, radiation and cytoreductive combination chemotherapy. Despite intensification of these aggressive therapeutic approaches, the overall outcome of RMS has also improved only modestly, with overall survival rates rising from 49% in 1975-1979 to 66% in 2005-2011. In fact, improvement in 5-year survival for RMS has seen one of the smallest increases in all of childhood cancer. A dramatic outside-of-the-box approach is sorely needed for both devastating diseases. Cryoablation is a readily available clinical intervention where ultra-cold temperature within the tumor is achieved by passing argon gas or liquid nitrogen via a probe. Tumor cells damaged by the formation of liquid crystals release danger-associated molecular patterns, thereby activate the STING/cGAS pathways in the myeloid cells and enhance anti-tumor immune responses to result in tumor reduction in both the treated and untreated, distant lesions (abscopal effect). Using a mouse model of RMS, we have uncovered a novel role of tumor-intrinsic STING/cGAS signaling in orchestrating the magnitude of antitumor immune response following cryoablation, thereby uncovered a potential novel biomarker of therapy response. Our project aims to further investigate the role of tumor cell-intrinsic STING/cGAS pathway in OS and provide the immunological mechanisms underlying this novel treatment methods for both RMS and OS, with an urgency to translate this knowledge into a sarcoma clinical trial combining cryoablation and immunotherapy.