Figure 3.

CTLA-4 and PD1/PD-L1 blockade using immune checkpoint inhibitors. Dendritic cells process and present tumor neoantigens through the MHC to the TCR on T-cells in the draining lymph nodes. T-cell activation further requires a co-stimulatory signal by CD80-CD28 binding. Upon T-cell activation, CTLA-4 can be upregulated in T-cells. CTLA-4 has a higher affinity towards CD80 than CD28; therefore, the overexpression of CTLA-4 interferes with the co-stimulatory CD80-CD28 signal preventing T-cell activation. Ipilimumab prevents this mechanism by binding to CTLA-4 thus blocking its interaction with CD80. Once activated T-cells migrate to the tumor to mount an immune anti-tumor response, tumor cells and macrophages can upregulate PD-L1 and suppress the immune response by interacting with the upregulated PD-1 on T-cells. Anti-PD1 and anti-PD-L1 antibodies inhibit this adaptive immune resistance mechanism.

Abbreviations: CTLA-4, cytotoxic T-lymphocyte-associated antigen; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; MHC, major histocompatibility complex; TCR, T cell receptor.