Understanding the impact of STING agonists on the tumor microenvironment in pediatric sarcomas
Mentor Name: Brian Ladle
Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. New approaches are desperately needed to improve the standard chemotherapy regimen of Methotrexate, doxorubicin (Adriamycin), and cisPlatin (MAP). Our lab has been investigating intratumoral (IT) delivery of ADU-S100, a stimulator of interferon genes (STING) agonist, in a groundbreaking canine OS clinical trial and in murine OS models. In our murine models, we have observed remarkable anti-tumor responses, including complete tumor regression, when ADU-S100 is given in combination with chemotherapy. We hypothesize that incorporating this potent immunotherapy with upfront MAP will both augment the chemotherapy cytotoxicity and generate potent innate and T cell immune responses against the cancer cells, resulting in improved treatment outcomes. The cGAS-STING pathway is a cell-intrinsic innate immune sensor that induces inflammatory gene programs in response to aberrant double-stranded DNA from infection or DNA damage. In cancer, the pathway can be activated by mechanisms such as chromosomal instability or DNA-damaging chemotherapy agents. In our clinical trial of canine OS, IT ADU-S100 causes profound local effects on the tumor microenvironment (TME), recruiting cytotoxic T cells, activated myeloid cells, and B cells to the normally “immune-cold” TME. We thus hypothesized that ADU-S100 with DNA-damaging carboplatin would further enhance immune activation against OS tumor cells. Indeed, treating OS tumor-bearing mice with IT ADU-S100 and systemic carboplatin significantly improves tumor rejection, with complete tumor regression in up to 40% of dual-treated mice. While the STING pathway’s role in cancer is complex, our preclinical results demonstrate a powerful effect of ADU-S100 with carboplatin on OS tumors that warrants further investigation. We will explore why only a portion of the mice in our experiments respond to the STING + chemotherapy treatments. We will compare the cell signaling and immune cell functions, comparing tumors in regressing versus progressing treated tumors using IHC and flow cytometry to analyze the immune cell differences in the tumors. As not all tumors respond to treatment equally, it provides a platform to compare “responder” tumors versus “non-responder” tumors in the same experiment. We seek to determine a “signature” of responder versus non-responder tumors indicating key factors driving response, as well as inhibitory factors that, if targeted, can further increase response rates.
