Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?

Figure 1 Cytotoxic T lymphocyte-associated protein 4 and programmed cell death-1 biological functions and therapeutic targeting. Cells of the immune system express several surface molecules that are important for immune surveillance and regulation of the immune response. T cell receptor (TCR) is expressed by T cells; it is an antigen-specific molecule that is unique to each T cell clone. Major human compatibility (MHC) molecule is expressed by antigen-presenting cells (e.g., dendritic cell) and display a potential tumor antigen for recognition by the specific TCR. Left panel: When an antigen presented in the context of MHC is recognized by the TCR, interaction of CD28 (expressed by T cell) with B7 (CD80/CD86) molecules provide a co-stimulatory signal leading to T-cell activation. However, depending on the conditions and microenvironment, these T cells can also express various levels of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), a regulatory receptor (immune checkpoint) with a higher binding affinity for B7 than CD28. Therefore, when CTLA-4 is available at the cell surface, it successfully competes for binding with B7, removing the co-stimulatory signal and leading to T-cell downregulation. Tumor cells can then escape the T cell cytotoxic effect (immune evasion). CTLA-4 blockade affects the immune priming phase occurring in the lymph node, by supporting the activation and proliferation of a higher number of effector T cells, regardless of TCR specificity, and by reducing Treg-mediated suppression of T-cell responses. Right panel: T cells also express PD-1 receptor, which has the potential to induce a programmed-death cascade in T cells that mistakenly react to host cells and thereby maintaining self-tolerance. PD-1 ligand, PD-L1, is used by tumor cells to engage the PD-1 receptor and switch off the reaction, inducing immune tolerance to the MHC-presented antigen. PD-L1 can also be expressed by stromal cells (e.g., M2 macrophages). PD-1 blockade works during the effector phase in peripheral tissues (tumor) to restore the immune function of “exhausted” T cells that have been turned off following extended or high levels of antigen exposure. CTLA-4: Cytotoxic T lymphocyte-associated protein 4; DC: Dendritic cell; MHC: Major human compatibility; PD-1: Programmed cell death-1; PD-L1: Programmed death-ligand 1; TCR: T cell receptor.