SUMMARY We propose developing a systems-biology approach to understand interactions between tumor and immune cells and their clinical implications. Our work will focus on medulloblastoma, a malignant pediatric brain tumor in which our team has extensive expertise. We and others have shown that medulloblastoma tumors are sites of immune activity despite the blood-brain barrier. However, the clinical consequences of these immune cells are unclear and there is little information that might guide development of therapeutics that modulate these immune cells. Our innovative strategy combines single-cell methods, including single-cell proteomics, with a sophisticated computational analysis. In Aim 1, we map the landscape of tumor-immune interactions using sequencing and imaging methods on human samples. Aim 2 builds a causal model of the molecular interactions that govern interactions among cell types in medulloblastoma, determines the clinical correlates of these cells, and identifies potential therapeutic targets. Aim 3 maps the tumor-immune environment in well-validated mouse models of the disease, and builds computational models for mice parallel to those for humans. Hypotheses from Aim 2 that are likely to translate well to the mouse models are then tested for their effects on tumor growth and survival. The mouse results are used to update the computational models and refine the therapeutic strategies. We expect that successful completion of this project will have a substantial impact on medulloblastoma therapeutics. Further, the methods we develop will catalyze research of interactions between immune cells and many other tumor types beyond medulloblastoma.

NARRATIVE Medulloblastomas are one of the most common pediatric brain tumors, and they have not benefited from recent dramatic advances in treating cancer by activating the immune system. Our study proposes developing a detailed molecular and cellular understanding of how these tumors interact with the immune system. Through computational modeling of these data, we will seek approaches that could alter the immune system to benefit medulloblastoma patients.