• PD1/PD-L1:

The PD-1 and PD-L1 checkpoints limit the excessive immune response to antigens and prevent autoimmunity. PD-1 is expressed in different immune cells such as NK cells, B-lymphocytes, T-lymphocytes, DC and activated monocytes. PD-L1 is overexpressed on tumour cells and promotes cancer avoidance of immune surveillance by inhibiting CTLs. The PD-1/PD-L1 pathway modulates immunosuppression by the following mechanisms: (1) the binding of PD-L1 on the surface of tumour cells and myeloid-derived suppressor cells (MDSCs) to PD-1 on the surface of tumour-specific T cells induces apoptosis and depletion of TIL in MSD; (2) activated PD-1 prevents T cells from proliferating, by selectively inhibiting RAS/MEK/ERK and PI3K/AKT signalling pathways, blocking cell cycle-related gene transcription and protein expression; (3) the expression of PD-L1 on the surface of APCs promotes the transformation of CD4+ T cells into induced Tregs (iTregs) and maintains immunosuppressive function by down-regulating the levels of mTOR, AKT, S6 and ERK2 phosphorylation and up-regulating the expression of PTEN in CD4+ T cells. This is the reason why blocking the PD-1/PD-L1 signalling pathway is expected to restore the function of the effector CD8+ T cells, while suppressing the function of the Tregs and MDSCs, improving the anti-tumour effect of the immune system [46].

This type of immunotherapy has been approved by the FDA for the treatment of melanoma, non-small cell lung cancer, colon and rectal cancer, Hodgkin's lymphoma, Merkel cell carcinoma, head and neck cancer, and bladder cancer [77].

• Combination of immune checkpoint inhibitors (ICIs):

The synergistic combination of monoclonal anti-CTLA-4 and anti-PD-1 antibodies is also used for the treatment of advanced melanoma, metastatic colorectal cancer that is deficient in highly unstable microsatellite repair, and colon and rectal cancer, as it has been shown to improve the overall patient response rate. For this reason, cytokines are being included in combined clinical trials with monoclonal anti-PD-1 and anti-PD-L1 antibodies [77].

On the other hand, the use of immune checkpoint inhibitors presents some problems, such as the appearance of primary and adaptive resistances to ICI monotherapy in some patients. It is therefore important to combine ICIs with other types of anti-tumoral treatment such as chemotherapy or radiotherapy, thus increasing their effectiveness. Another limitation is that some cancers do not respond to PD-1/PD-L1 immunotherapy and systemic administration of these inhibitors has immune-related adverse effects (irAE) [46].

Since the approval of ipilimumab, a CTLA-4-blocking antibody, by the FDA in 2011 for the treatment of metastatic melanoma [164], six other checkpoint inhibitory antibodies, in this case targeting the PD-1/PD-L1 axis, have been approved: nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, and avelumab. These ICIs act on a wide range of cancers: melanoma, NSCLC, hepatocellular carcinoma, squamous cell head and neck carcinoma, Hodgkin's lymphoma, urothelial carcinoma, etc. [165–168]. In 2015, the FDA approved the combination of ipilimumab with nivolumab (anti-PD-1 antibody), as it showed an improved response rate compared to any monotherapy in the treatment of melanoma [169]. In addition, there are several active clinical trials of ICI combination therapies [170,171]. The identification and validation of more reliable biomarkers would allow for more appropriate selection of patients with cancer that would improve the response rate [172].
