Combination Therapy Promotes IFN-Β Production in Sarcomas via the cGAS-STING Pathway

Overview

Osteosarcoma (OS) and rhabdomyosarcoma (RMS) are the most common malignant bone and soft-tissue sarcomas in children and adolescent young adults (AYA). Although the standard of care, which includes surgery, chemotherapy, and radiation therapy, has a 5-year survival rate of 70% for localized sarcomas, the rate drops to 30% upon metastasis. Cryoablation, an alternative treatment using freeze-thaw cycles on tumors, has the potential to increase the overall survival time of these patients. Cryoablation leads to the tumor's cold-induced necrosis, which releases immune activation molecules into the microenvironment and activates the cGAS-STING pathway. Previous studies have shown that cryoablation reduces tumor size and metastases in murine models of RMS. However, when human OS and RMS models were treated with STING agonists, the cGAS-STING pathway was not fully activated in vitro. Recent studies have shown that combination therapy using a STING agonist and a chemotherapeutic agent significantly enhanced IFN-β production in models of triple-negative breast cancer. To determine if a similar result would occur in sarcoma, human RMS cell lines were treated with a combination of next-generation STING agonists, MSA-2 and diABZI, and a microtubule destabilizer, vinorelbine. Treatment with vinorelbine alone increased IFN-β expression, but when combined with a STING agonist, the resulting IFN-β expression was more than double in one of the sarcoma cell lines. These findings suggest that combination therapy using chemotherapeutics and STING agonists may promote increased IFN-β production to combat sarcoma. Future studies will test additional combination therapies to increase the effectiveness of cryoablation.

Competition history

• AJAS 2024 Category not listed

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