The PD1:PD-L1/2 Pathway from Discovery to Clinical Implementation

Abstract

The immune system maintains a critically organized network to defend against foreign particles, while evading self-reactivity simultaneously. T lymphocytes function as effectors and play an important regulatory role to orchestrate the immune signals. Although central tolerance mechanism results in the removal of the most of the autoreactive T cells during thymic selection, a fraction of self-reactive lymphocytes escapes to the periphery and pose a threat to cause autoimmunity. The immune system evolved various mechanisms to constrain such autoreactive T cells and maintain peripheral tolerance, including T cell anergy, deletion, and suppression by regulatory T cells (TRegs). These effects are regulated by a complex network of stimulatory and inhibitory receptors expressed on T cells and their ligands, which deliver cell-to-cell signals that dictate the outcome of T cell encountering with cognate antigens. Among the inhibitory immune mediators, the pathway consisting of the programed cell death 1 (PD-1) receptor (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) plays an important role in the induction and maintenance of peripheral tolerance and for the maintenance of the stability and the integrity of T cells. However, the PD-1:PD-L1/L2 pathway also mediates potent inhibitory signals to hinder the proliferation and function of T effector cells and have inimical effects on antiviral and antitumor immunity. Therapeutic targeting of this pathway has resulted in successful enhancement of T cell immunity against viral pathogens and tumors. Here, we will provide a brief overview on the properties of the components of the PD-1 pathway, the signaling events regulated by PD-1 engagement, and their consequences on the function of T effector cells.

PDCD5 regulates cell proliferation, cell cycle progression and apoptosi

“…Among them, PDCD8 and PDCD9 are officially known as AIFM1 and MRPS30, respectively. PDCD1, often known as PD-1, is the member that has been most extensively studied and shown to negatively regulate T cell responses, in collaboration with its two ligands, PD-L1 and PD-L2 (51)(52)(53). In addition to PDCD5, other programmed cell death proteins are also known to play important roles in apoptosis and/or cell cycle progression (54)(55)(56)(57), and are also dysregulated in many types of human cancers (13,16,(58)(59)(60)(61)(62)(63).…”

High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome

“…(29) 11 (19) 102 (31) 86 (31) 25 (25) No 205 (53) 35 (62) 170 (52) 148 (53) 55 (53) Missing 69 (18) 11 (19) 58 (18) 46 (16) 22 (22) Lymphocyte count .02…”

“…Expression of PD-L1 is restricted to antigenpresenting cells, but may also be expressed by B and T lymphocytes, NK cells, monocytes, dendritic cells, and mast cells following exposure to proinflammatory cytokines. 24,25 PD-L2 expression is mainly restricted to dendritic cells and macrophages and is not induced by inflammatory cytokines. 24 PD-L1 is probably the main inducer of immunosuppression in malignant conditions because of its inducible capacity, 24 something that might also explain why PD-L2 was not associated with outcome in our cohort.…”

“…Yes 105 (28) 14 (25) 91 (28) 86 (31) 17 (17) No 261 (67) 38 (66) 223 (67) 180 (64) 78 (76) Missing 21 (5) 5 (9) 16 (5) 14 (5) 7 (7) B symptoms .…”

RET-mediated modulation of tumor microenvironment and immune response in multiple endocrine neoplasia type 2 (MEN2)

“…Immune checkpoint blockade therapies that inhibit CTLA-4-CD80/CD86 and/or the PD-1/PD-L1 axis have proven successful in treating several cancers (Bardhan et al 2016). However, the expression levels of immune checkpoints in tumors are not always predictive of therapeutical response.…”