Fig. 1

Restoring T-cell activation through the use of checkpoint inhibitors. a Naïve T cells become activated following their recognition of peptides presented in the context of MHC molecules expressed on the surface of antigen presenting cells, such as dendritic cells, along with engagement of costimulatory molecules (B7) with CD28 and this activation results in upregulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that outcompetes CD28 for binding to B7 on antigen presenting cells in order to block T cell responses. Another inhibitory pathway uses the programmed cell death 1 (PD-1) receptor. CTLA-4 and PD-1 modulate different aspects of the T cell response. CTLA-4 is rapidly induced in T cells, following activation via MHC/TCR and B7/CD28 mediated signaling. In contrast, the major role of the PD1 pathway is to regulate inflammatory responses in tissues by effector T cells recognizing antigen in peripheral tissues. b Cancers can express the ligands for these checkpoint molecules, thus blocking T cell responses. Thus, the use of checkpoint inhibitors allow T cells to maintain their effector functions via the secretion of cytokines that recruit other immune cells to participate in the antitumor response and through their cytolytic capabilities. Numerous checkpoint inhibitors are currently being used in the clinic. CTLA-4, cytotoxic T-lymphocyte antigen; PD-1, programmed death 1; PD-L1, programmed death ligand 1; APC, antigen presenting cell; MHC, major histocompatibility complex; TCR, T cell receptor