Figure 3.

PD-1/PD-L1/PD-L2 pathway hijacking in oncology. Immune checkpoints are exploited by solid tumors to evade or suppress the immune system. The PD-1/PD-L1 co-inhibition axis, within the tumor microenvironment, will allow many PD-L1 tumor cells to escape the immune system through multiple mechanisms. One of these is the decrease of effector functions of cytotoxic TLs, directed against the tumor antigen by inducing their functional depletion (exhaustion), reducing their cytokines (IL-2) production ability, their high proliferation capacity, their cytotoxic activity and consequently the resistance to tumor cell lysis. The second step is the functional alterations in the production of TNFα, IFNγ, β−chemokines, and degranulation. In the most terminal stages of depletion, these cells may enter apoptosis, probably as a consequence of over-stimulation. PD-L1 role is also to maintain and induce tumor-associated regulatory T-cells (induced Tregs), by promoting their switching from naive CD4+ TLs. Infiltration of their microenvironment by activated TLs producing pro-inflammatory cytokines such as IFNγ enhances PD-L1 upregulation in tumor cells. This feedback loop is thought to be a mechanism of adaptive immune resistance by the tumor. APC, Antigen Presenting Cell; CTLA-4, Cytotoxic T lymphocyte-associated Antigen 4; IFNγ, Interferon Gamma; IL-2, Interleukine 2; MHC, Major Histocompatibility Complex; PD-1, Programmed Death 1; PD-L1, Programmed Death Ligand 1; TCR, T-cell Receptor; TIL, Tumor-infiltrating Lymphocyte; TNFα, Tumor Necrosis Factor Alpha; Treg, Regulatory T lymphocyte.