Deciphering the role of Microglia in Glioblastoma

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Glioblastomas are the most common primary malignant brain tumors. Total neurosurgical resection of glioblastomas is not possible, and tumors invariably recur even following resection, chemotherapy and radiotherapy. Despite extensive research into the biology of glioblastomas, there has been no change in the standard of care for ~20 years and the median lifespan from time of diagnosis to death remains dismal at ~15 months. This highlights the need for identifying new targets for therapy of these devastating tumors. Glioblastomas are characterized by extensive infiltration of microglia; the main resident innate immune cells of the brain. Yet, despite their large presence, microglia fail to keep the tumor in check and appear to promote tumor growth. The exact mechanism(s) of this pro-tumor role of microglia remain incompletely understood. Using an approach that allows us to selectively identify and isolate microglia present within the tumor (vs. those in the same brain but outside the tumor), we determined the transcriptomes of these Glioblastoma Associated Microglia (GAMi) by RNASeq in a murine model of glioblastoma. We found that glioblastomas reprogram microglial transcriptional networks by downregulating pathways potentially involved in recognizing and killing tumor cells. Specifically, we found that GAMi have downregulated: (a) genes potentially involved in immune sensing and phagocytosis of glioblastoma cells and (b) transcripts potentially involved in direct tumor killing. We also found that most of the changes observed in GAMi may be driven by a microglia specific pathway. We obtained similar findings when we analyzed datasets from human glioblastoma patients. In this application, we propose to test which of these microglial transcriptional changes are functionally important in regulating tumor growth using three preclinical mouse glioblastoma models and a co-culture model of patient-derived human glioblastoma and iPSC-derived microglia. We will also identify the precise microglial pathway(s) that regulates these processes. To achieve this, we propose three specific aims. In aim 1, we will determine if GAMi have reduced functional capacity to recognize and phagocytose tumor cells, and the effect of such reduced capacity on tumor growth. In aim 2, we will determine if GAMi have reduced functional capacity to kill tumor cells, and the effect of such reduced capacity on tumor growth. In aim 3, we determine the specific microglial pathway that regulates microglial sensing and phagocytosis of glioblastoma cells, direct killing of tumor cells and whether targeting such pathway will regulate overall tumor growth. Our studies would provide proof of concept that these pathways can be used as potential effective targets for therapy of this devastating tumor.