Fig. 2

The GBM immunity cycle and associated treatments. The immune response in GBM can be divided into six steps, starting with antigen release from GBM cells and ending with the killing of GBM cells. Potential treatments impacting the immune response steps are written in blue. Step 1 – Antigens are released from dying GBM cells. Step 2 – Tumor antigens are captured by APCs, processed and displayed on MHC-I and -II molecules for presentation to T cells. Step 3 – Effector T cells are primed and activated in response to tumor antigen presentation. Step 4 – Activated T cells traffic through the BBB and infiltrate the tumor site. Step 5 – The immunosuppressive TME must be overcome to allow activated T cells to recognize and bind to GBM cells. Step 6 – Activated T cells kill GBM cells after binding to GBM tumor antigen on MHC-I through the T cell receptor (TCR). The boxes * and ** represent the CTLA-4 and PD-1/PD-L1 pathways. * T cells are activated after the binding of TCR with antigens displayed on MHC and the simultaneous CD28:CD80/86 costimulatory signal. CTLA-4 mediates T cell inhibition by competitively binding to CD80/86. ** T cells are activated after recognizing GBM cells, secreting inflammatory cytokines and inducing GBM cell death. PD-1:PD-L1 binding induces T cell inhibition by reducing T cell proliferation and cytokine production. (Abbreviations: APC = Antigen-presenting cell; Chemo = Chemotherapy; CTLA-4 = Cytotoxic T-lymphocyte antigen 4; CXCR4 = C-X-C chemokine receptor 4; GBM = Glioblastoma; GITR = Glucocorticoid-induced tumor necrosis factor-related protein; IDO = Indoleamine 2,3-dioxygenase; LAG-3 = Lymphocyte activation gene 3 protein; MDSC = Myeloid-derived suppressive cell; MHC = Major histocompatibility complex; PD-1 = Programmed cell death-1; PD-L1 = Programmed death ligand-1; RT = Radiotherapy; TAM = Tumor-associated microglia and macrophage; TCR = T cell receptor; TIGIT = T cell immunoreceptor with Ig and ITIM domains; TIM-3 = T cell immunoglobulin and mucin domain containing-3; VEGF = Vascular endothelial growth factor)