Brain Tumor Micro-environment and Host State - Implications for Immunotherapy

Glioblastoma (GBM) is a highly lethal brain tumor with poor responses to immunotherapies which have been successful in more immunogenic cancers with less immunosuppressive tumor microenvironments (TMEs). GBM's TME is uniquely challenging to treat due to tumor cell extrinsic components that are native to the brain, as well as tumor intrinsic mechanisms which aid in immune evasion. Lowering the barrier of immunosuppression by targeting the genetically stable tumor stroma presents opportunities to treat the tumor in a way that circumvents the complications of targeting a constantly mutating tumor with tumor antigen directed therapies. Tumor associated monocytes, macrophages, and microglia (TAMs) are a stromal element of particular interest. Macrophages and monocytes compose the bulk of infiltrating immune cells and are considered to have pro-tumor and immunosuppressive effects. Targeting these cells or other stromal elements is expected to convert what is considered the "cold" TME of GBM to a more "hot" TME phenotype. This conversion could increase the effectiveness of what have become conventional frontline immunotherapies in GBM - creating opportunities for better treatment through combination therapy.

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