Glioblastoma usurps host extracellular adenosine to circumvent host anti-tumor Responses

Abstract

Abstract Glioblastoma (GB) is the most aggressive, fatal, and least successfully treated of all solid brain tumors due to its high capacity to proliferate and extreme chemoresistance. Treatment for GB patients is managed with multimodal therapies including surgical resection (if possible), radiotherapy and chemotherapy with temozolomide (one of the few drugs shown to have some effect). Despite this, patient survival ranges between 6–18 months. Because GB is highly infiltrative, it often invades normal brain tissue, sometimes preventing surgical resection, which inevitably leads to recurrence. Adenosine is an immune suppressive signaling molecule that is generated by the enzymatic action of CD73. I tested the hypothesis that GB usurps host extracellular adenosine to circumvent host anti-tumor mechanisms by down regulating macrophage/microglial cell immune responses and promote M2 instead of M1 macrophage/microglial phenotype. To test this, I isolated macrophage/microglial cells from the tumor microenvironment of mice lacking or expressing CD73. Compared to WT mice, the frequency of M1 verses M2 phenotypes showed that eighty percent of the macrophage/microglial cells present in the tumor microenvironment of CD73−/− mice exhibited an M1 phenotype, while WT mice had about 30 percent M1 phenotype.