Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.58 Figure 1 Immune checkpoints and control of T-cell activation in melanoma Figure 1 | Immune checkpoints and control of T-cell activation in melanoma. a | Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) modulate the T-cell immune response at different levels. The priming of naive T cells is initiated by antigen-presenting cells (APCs) such as Langerhans cells. These cells collect tumour-associated antigens (TAAs) located in the primary melanoma and migrate through afferent lymphatics to the skin-draining lymph nodes, where they present TAAs to naive T cells, thereby initiating T-cell maturation and a specific immune response. Naive T cells permanently circulate between the blood and the lymphoid organs and extravasate through the high endothelial venules (HEV) to enter the T-cell dependent area of the draining lymph nodes, where they might encounter their specific antigen presented by APCs. b | Two signals are required to activate naive T cells to become memory T cells: Signal 1; antigen recognition by the T-cell receptor (TCR), Signal 2; co-stimulation. After 48–72 hours, CTLA-4 is expressed on the surface of activated T cells, which continues the co-stimulatory interaction and suppresses T-cell activation. Memory T cells have distinct adhesion molecules that allow them to circulate to peripheral tissues and melanoma metastases, and to be reactivated upon antigen re-encounter. c | In metastatic melanoma, T-cell activation is decreased when PD-1 binds to its ligands programmed cell death 1 ligand 1 (PD-L1) and/or PD-L2, which can be expressed by tumour cells and/or immune cells present in the tumour microenvironment. CTLA-4 also suppresses the activity of T cells in the metastases by enhancing the immunosuppressive activity of regulatory T (TREG) cells, which express high levels of CTLA-4. Antibodies against CTLA-4 act at the initiation of the immune response by maintaining T-cell activation in the lymph nodes as well as at the tumour site, by decreasing TREG cells via antibody-dependent cell-mediated cytotoxicity (ADCC) after binding of anti-CTLA-4 antibodies to both TREG cells and to the FcγRIIIA of (CD16+) tumour-associated monocytes/macrophages (TAM). Anti-PD-1 antibodies induce T-cell reactivation by preventing binding of PD-1 with its ligands at the tumour site. MHC, major histocompatibility complex; TCR, T-cell receptor. From the New England Journal of Medicine, Robert, C. & Kupper, T. S. Inflammatory skin diseases, T cells, and immune surveillance 341, 1817–1828. Copyright © (1999) Massachusetts Medical Society. Modified with permission. From the New England Journal of Medicine, Robert, C. & Kupper, T. S. Inflammatory skin diseases, T cells, and immune surveillance 341, 1817–1828. Copyright © (1999) Massachusetts Medical Society. Modified with permission. Boutros, C. et al. (2016) Safety profiles of anti-CTLA‑4 and anti‑PD‑1 antibodies alone and in combination Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2016.58