Gastrointestinal Stromal Tumor (GIST) and the Immune System
Our laboratory discovered that imatinib changes the intratumoral immune environment by activating cytotoxic CD8+ T cells and inducing apoptosis of anti-inflammatory regulatory T cells through the inhibition of tumor-derived Ido. The immune-mediated anti-tumor effects of imatinib are enhanced when combined with immunotherapy such as CTLA-4 blockade, which led to a clinical trial in human GIST patients. Other cells in the tumor microenvironment, including macrophages, DCs, and stromal cells, also mediate tumor growth and destruction. We seek to better understand the role of the immune system in GIST, with the intention of developing novel molecular and immune-based treatment strategies.
Nearly 75% of GISTs contain an activating Kit mutation, while 10% have a mutation in platelet derived growth factor receptor alpha (PDGFRa). Imatinib inhibits both Kit and PDGFRa oncoproteins and has improved survival in metastatic GIST, but patients eventually develop resistance and tumor progression.
We have studied the effect of imatinib on Kit signaling and on various compensatory oncogene signaling pathways, including MET. Currently, we are interested in the role of endogenous Kit ligand signaling in the presence of a constitutively active mutation with respect to imatinib resistance.