Challenges in Immunotherapy Presented by the Glioblastoma Multiforme Microenvironment

Figure 1

Normal T cell proliferation and mechanisms of glioma cell immunoresistance. (From top moving clockwise) Normal T cell proliferation: tumor cell antigens are presented by MHC and costimulatory molecules. Mechanisms of immunosuppression: glioma cells secrete factors leading to an immunosuppressive tumor microenvironment. TGFB and PGE-2 downregulate the expression of MHC, restricting antigen presentation and T cell proliferation. IL-6. IL-10 and VEGF are potent STAT-3 activators, leading to the proliferation of immature DCs that are not able to function as APCs. These immature DCs also secrete TGFB which aid in the proliferation of immunosuppressive Treg cells and STAT-3 positive TH17 cells. Mechanisms of inhibiting T cell proliferation: glioma cells downregulate MHC on their surface leading to the decreased antigen presentation and decreased T cell proliferation. Downregulation of B7 works via a similar mechanism in that the costimulatory signal is lost preventing T cell proliferation. Increased expression of B7-H1 and FasL act as proapoptotic signals for T cells.