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Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system

2015; Elsevier BV; Volume: 21; Issue: 8 Linguagem: Inglês

10.1016/j.molmed.2015.05.005

1471-499X

Yago Pico de Coaña, Aniruddha Choudhury, Rolf Kiessling,

Immunotherapy and Immune Responses

•Immune checkpoints dampen T cell activation, avoiding excessive immune responses. •CTLA-4 and PD-1 are currently the two most clinically relevant immune checkpoints. •Checkpoint blockade acts by activating the immune system to eliminate tumors. •Checkpoint-blockade therapies have shown impressive increases in overall survival. Immune checkpoint receptors are crucial molecules for fine-tuning immune responses. Checkpoint signaling dampens T cell activation to avoid autoimmunity and the destructive effects of an excessive inflammatory response. It is well established that tumors use several mechanisms to avoid elimination by the immune system, and one involves hijacking these checkpoint pathways. Checkpoint blockade therapy utilizes monoclonal antibodies to release the brakes from suppressed T cells, allowing them to be activated and recover their antitumor activity. This therapeutic approach has revolutionized cancer immunotherapy, and extraordinary increases in overall survival were noted, first with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) and subsequently with anti-PD-1 (programmed cell death receptor-1) in melanoma and other malignancies. Immune checkpoint receptors are crucial molecules for fine-tuning immune responses. Checkpoint signaling dampens T cell activation to avoid autoimmunity and the destructive effects of an excessive inflammatory response. It is well established that tumors use several mechanisms to avoid elimination by the immune system, and one involves hijacking these checkpoint pathways. Checkpoint blockade therapy utilizes monoclonal antibodies to release the brakes from suppressed T cells, allowing them to be activated and recover their antitumor activity. This therapeutic approach has revolutionized cancer immunotherapy, and extraordinary increases in overall survival were noted, first with anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) and subsequently with anti-PD-1 (programmed cell death receptor-1) in melanoma and other malignancies. any type of cell that can process antigens and present them to T cells in conjunction with MHC and other costimulatory molecules, typically leading to the activation of T cells. a costimulatory receptor expressed on the surface of T cells. It is responsible for the second signal of T cell activation after peptide recognition by the TCR. a protein expressed mainly on the surface of T cells that transmits inhibitory signals when bound to its ligands, CD80 and CD86. a group of inhibitory pathways in the immune system whose function is maintaining self-tolerance and modulating the immune response to avoid tissue damage and autoimmunity. a set of molecules expressed on all nucleated cells and at high levels on APCs that are crucial for antigen-specific activation of T cells. a heterogeneous group of cells of myeloid origin that possess immune suppressive activity. a surface protein, expressed on T cells and B cells. It transmits inhibitory signals when bound to its ligands PD-L1 and PD-L2. a subset of CD4+ T cells with immune-modulatory properties. In healthy individuals they maintain tolerance to self-antigens and abrogate autoimmune diseases. a receptor expressed on the surface of T cells. Each TCR specifically recognizes unique peptides displayed on MHC molecules, thus providing the T cell with the initial activation signal, signal 1. an antigenic protein produced by tumor cells that has the potential of triggering an immune response in the host. lymphocytes found inside tumors or in the tumor stroma. Although they can also include B cells and natural killer (NK) cells, the term usually refers to CD4+ and CD8+ T cells.