Reprograming the innate immune system against glioma

Cancer immunotherapy research is rapidly advancing, with immune-checkpoint inhibitors showing particular promise. Tumor associated macrophages/microglia (TAMs) are an abundant immune infiltrate, which can be co-opted into a polarized, tumor-supportive state, and contribute significantly to immunosuppression. Status-quo approaches target TAM survival. But, both myeloid-derived macrophages and brain-resident microglia are targeted equally. Current strategies don’t distinguish tumor-supportive TAMs from those that play an anti-tumor role. And, surprisingly little is known about how mutations in the tumor influence tumor-TAM interaction. Our goal is to identify gene targets specific to tumor-supportive TAMs, and find functional mutations mediating TAM-tumor synergy. 

We employ high-throughput, single-cell transcriptomics and proteomics of TAMs derived from primary, human GBMs. Using state-of-the-art machine-learning we have identified a spectrum of TAM states. These range from classically activated macrophages/microglia to TAMs down-regulating class II HLA, and up-regulating immunosuppressive cytokines and immune-checkpoint genes. Using non-malignant human microglia and bone-marrow monocytes as controls, we are identifying pathways governing distinct responses of these cell types to the tumor microenvironment.

We combine these high-throughput assays with CRISPR-interference, small-molecule and other molecular assays in vitro and in mouse. Our goal is a high-resolution map of the TAM polarization states in GBM, the identification of tumor mutations that correlate with the expression of TAM immunosuppressive factors and pre-clinical evidence for specific targets mediating TAM immunosuppression.