The Impact of the Innate Immune System in Alveolar Soft Part Sarcoma
Alveolar Soft Part Sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes, largely due to a complete lack of chemotherapeutic treatment options, and a high likelihood of metastasis. Further, a lack of pre-clinical models has hampered progression in the understanding of the tumor’s biology and resistance to chemotherapies since it was originally described in 1952. After being in the privileged position of receiving ASPS tumor tissue from the lung metastasis of a 14-year-old female, the Senger laboratory successfully established an ASPS patient derived xenograft (PDX) model and corresponding cell line. Recent literature has suggested that the tumor microenvironment (TME) is implicated in the tumor progression of multiple soft tissue sarcomas, including ASPS; specifically, macrophage have been described as a prominent prognostic marker. Therefore, using this PDX model, we characterized the innate immune component of the TME with respect to the cell populations and cytokines secreted by both the tumor cells and stroma. Unsurprisingly, the PDX tumors were abundant in pro-tumor macrophage and pro-inflammatory cytokines. As data generated by the Senger laboratory had established the susceptibility of ASPS cells to proteasome inhibitor carfilzomib, carfilzomib was also evaluated for its anti-tumor implications on both the tumor cells and the innate immune microenvironment. After observing a number of anti-tumor changes to the macrophage within the TME following carfilzomib treatment, this chemotherapeutic significantly decreased tumor burden in ASPS PDX bearing mice suggesting the TME may be the Achille’s heel to this chemotherapy resistant sarcoma.
Sarcoma, Tumor Microenvironment, Macrophage, Proteasome Inhibitors
Philippot, A. M. (2022). The impact of the innate immune system in Alveolar Soft Part Sarcoma (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.