Altering the Tumor Microenvironment to Augment Neuroblastoma Immunotherapy
Abstract
We are working to combine precision immunomodulatory therapy with chemoimmunotherapy to improve outcomes for high-risk neuroblastoma, and create a paradigm shift in our therapeutic approach to this highly lethal disease. Current treatment includes chemotherapy, surgery, myeloablative transplant, radiotherapy and then immunotherapy at the time of minimal residual disease. Our goals here are to leverage immunotherapy efficacy by tailoring specific immunomodulators to specific immunosuppressive TMEs, which are strongly impacted by the specific oncogenes activated in the cancer. We are studying two transgenic murine neuroblastoma models driven by distinct oncogenes (MYCN and T-Ag). We are using CyTOF and flow-cytometry, supplemented by transcriptional and cytokine profiles, to characterize the tumor TME. In year 1 we have shown that MYCN-driven neuroblastomas sculpt an immunosuppressive TME, but that the use of DFMO (an immunomodulator) leads to marked changes in the proportions and activity states of tumor-infiltrating leukocytes. We see markedly enhanced numbers of NK cells, and they express higher levels of activating-type surface receptors (in contrast to inhibitory-type receptors). Further, tumor cells in DFMO treated animals show upregulated expression of surface NK cell ligands. Whether this is a major contributor to the anti-tumor effect of DFMO is not yet known. It is possible these NK cells are poised for engagement and tumor cell killing but are inhibited, and a possible inhibitory axis to explore includes the TGFb axis. The reason this is important is because if that were the case, then combining DFMO with a TGFb inhibitor might significantly augment the anti-tumor activity of the regimen. Parallel work in the alternative model is proceeding but is delayed relative to the MYCN model.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2019
- Accession Number
- AD1086492
Entities
People
- Shahab Azgharzadeh