Unwrapping the genomic characteristics of urothelial bladder cancer and successes with immune checkpoint blockade therapy

a Naive T-cell activation takes place after T-cell receptors recognize the major histocompatibility complex (MHC) presenting a specific tumor antigen (signal 1), and the interaction of between CD28 and B7 molecules (CD80 and CD86) (signal 2) expressed on the T-cell surface and on antigen-presenting cells, respectively. b T cells express immune checkpoint proteins such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death/programmed death-ligand-1 (PD-1/PD-L1). CTLA-4 binds B7 molecules with much higher affinity blocking co-stimulation; PD-1 binds the ligand of PD-1 expressed in many cell types, including tumor cells. Both signaling pathways downregulate T-cell responses and protect cells from activated T-cell attack. c The complex tumor microenvironment consists of various types of cells, including tumor cells, stromal cells, regulatory T cells, myeloid-derived suppressor cells (MDSC), and inhibitory cytokines, these inhibitory cells abrogate T-cell function and reduce antitumor immune responses. d Antibodies against immune checkpoint molecules and increase T-cell response