Revisiting the PD-1 pathway

Abstract

Programmed Death-1 (PD-1; CD279) is an inhibitory receptor induced in activated T cells. PD-1 engagement by its ligands, PD-L1 and PD-L2, maintains peripheral tolerance but also compromises anti-tumor immunity. Blocking antibodies against PD-1 or its ligands have revolutionized cancer immunotherapy. However, only a fraction of patients develop durable antitumor responses. Clinical outcomes have reached a plateau without substantial advances by combinatorial approaches. Thus, great interest has recently emerged to investigate, in depth, the mechanisms by which the PD-1 pathway transmits inhibitory signals with the goal to identify molecular targets for improvement of the therapeutic success. These efforts have revealed unpredictable dimensions of the pathway and uncovered novel mechanisms involved in PD-1 and PD-L1 regulation and function. Here, we provide an overview of the recent advances on the mechanistic aspects of the PD-1 pathway and discuss the implications of these new discoveries and the gaps that remain to be filled.

Immunosuppression in Gliomas via PD-1/PD-L1 Axis and Adenosine Pathway

“…It is known that PD-1 interaction provides T-cell inhibitory signals. PD-1/PD-L engagement during TCR stimulation leads to tyrosine phosphorylation of the PD-1 cytoplasmic tail on high affinity sites for SH2 domain-containing phosphatase (SHP-2 and SHP-1), resulting in the dephosphorylation of proximal signaling molecules which decrease T cell proliferation and survival by attenuate PI3K and Akt pathways ( 31 , 34 ).…”

Sintilimab: A Promising Anti-Tumor PD-1 Antibody

“…The ligands of PD-1 included PD-L1 and PD-L2 (12,13). The expression of PD-L2 on tumor cells is rare, and the role of PD-1/PD-L1 pathway in the regulation of anti-tumor immunity is more studied (14).…”

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

“…Further studies revealed that the physiologic role of PD-1 is not related to cell death, but it is instead involved in regulation of immune responses, as demonstrated by the development of lupus-like autoimmune diseases in PD-1-deficient mice [12,13]. PD-1 belongs to the CD28/Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) subfamily of the Immunoglobulin (Ig) superfamily [14] and it is a 50-55 kDa type I transmembrane glycoprotein [15]. PD-1 specifically binds the type I transmembrane proteins PD-L1 (B7-H1; CD274) [16,17] and PD-L2 (B7-DC; CD273) [18,19], both of which are B7 family members [20,21].…”