3.3.5. Checkpoints Inhibitors

T cells play a critical role in the recognition together with the effector cells of the acquired immune response, and their activation requires the presence of two signals: the antigen-specific signal, mediated by TCR and MHC, and the co-stimulatory signal, mediated by membrane protein molecules expressed on the surface of the T cells and their ligands. The co-stimulatory molecules of the T cell activation signals enhance the immune responses mediated by TCR signalling. These molecules initiate, stimulate, amplify and enhance the immune response at different stages, also controlling its extension and duration. In tumour tissues, negative regulatory checkpoints predominate, inhibiting T cell activation, thus allowing tumour cells to evade the immune response and generating an immune tolerance of the tumour. Therefore, immune checkpoints (ICs) are key to maintaining self-tolerance, protecting the body against autoimmunity and inflammation by interfering with the cytotoxic T cell (CTL) immune response. Pathways that inhibit the immune checkpoint are always activated in inflammatory MSDs, allowing tumour cells to evade immune surveillance, also eradicating the immune response of TILs. Different types of Immune Checkpoint Inhibitors (ICIs) have been developed to reactivate these dysfunctional T cells [46].

**Figure 9.** Inducing anti-tumour immune responses by dendritic cell (DC) vaccination through infusing patients with ex vivo antigen loaded DCs (left) or targeting antigens and adjuvants directly to DCs in vivo (right).

Checkpoint inhibitors are monoclonal antibodies that block CTLA-4 (Cytotoxic T-Lymphocyte-associated Antigen 4), PD-1 (Programmed cell Death receptor) or its ligand PD-L1 (Figure 10) [77].

**Figure 10.** Schematic representation of the mechanisms of immune-checkpoint inhibitors (ICIs).
