THE ROLE OF CD73 IN GLIOBLASTOMA PATHOGENESIS AND ANTI-GLIOBLASTOMA IMMUNE RESPONSE
CD73 is a key enzyme in extracellular ATP metabolism; it converts AMP to extracellular adenosine. CD73 is involved in many cellular functions, including cell adhesion, cell proliferation, tumor invasion, and angiogenesis. Because of its enzymatic activity, CD73 is also a key immune regulator. CD73-generated extracellular adenosine signals through the A2A adenosine receptor (AR) on leukocytes to attenuate inflammation and restore immune homeostasis. Because of these properties, CD73 is used by tumor cells to promote their pathogenesis and attenuate the host anti-tumor immune response. In this dissertation, we investigated the role of CD73 in glioblastoma (GB) pathogenesis and anti-GB immune response. We implanted mouse GB cells in wild type (WT) and CD73-/- mice. We found that GB-bearing CD73-/- mice had reduced tumor size and invasiveness and decreased tumor vessel density compared with GB-bearing WT mice. To investigate whether host CD73 promoted GB invasiveness, we generated the CD73-FLK mice from the CD73-/- mice by enforcing CD73 expression on endothelial cells. GB-bearing CD73-FLK mice had the most invasive tumors compared with GB-bearing WT and CD73-/- mice, suggesting that the limited host CD73 on endothelial cells increased GB invasiveness. We also found a 20-fold upregulation of the A2B AR in GB, which is rarely expressed in the central nervous system under physiological conditions and only upregulated during pathological conditions. Inhibition of A2B AR signaling decreased the permeability glycoprotein (P-gp) and the multidrug resistance-associated protein 1 (MRP1) expression on mouse GB cells and made GB cells more susceptible to temozolomide-induced cell death. Additionally, we found that GB-bearing CD73-/- mice mounted a stronger inflammatory response to GB than GB-bearing WT mice. Compared with GB-bearing WT mice, GB-bearing CD73-/- mice had increased anti-inflammatory cytokine IL-10 and reduced pro-inflammatory cytokines TNF-α and IL-1β. Further, GB-infiltrating regulatory T cells and M2 microglia/macrophages were reduced in GB-bearing CD73-/- mice, whereas GB-infiltrating CD8+ T cells were increased. Together, these findings suggest that CD73 is used by GB to promote its pathogenesis through increasing GB angiogenesis, invasion, and chemoresistance. Our data also suggest that GB evades the host immune response by using CD73 to attenuate inflammatory responses. Therefore, targeting the CD73-AR axis presents great potentials for future GB therapeutic interventions.
Immunology; A2B adenosine receptor; cancer immunology; CD73; extracellular adenosine; glioblastoma; glioma chemoresistance; Oncology
Bynoe, Margaret S.
Clark, Theodore G.; August, Avery; Rudd, Brian D.
Biomedical and Biological Sciences
Ph.D., Biomedical and Biological Sciences
Doctor of Philosophy
dissertation or thesis