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 (T_Regs). 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.

Keywords: PD-1; PD-L1; T cell exhaustion; T cell responses; T cell tolerance; cancer immunology; cancer immunotherapy.

Figure 1

Effect of PD-1 on major signaling pathways and subsequent metabolic reprograming in T cells. When T cell encounters a foreign antigen presented by MHC on the surface of APC, TCR gets phosphorylated upon oligomerization of TCR/CD3 chains, followed by recruitment of activated Lck and Zap-70 to the phosphorylated ITAM (tyrosine motifs) of TCR tail, leading to initiation of downstream TCR-signaling cascade. During TCR cross-linking, when PD-1 interacts with its ligands, the two tyrosine residues on PD-1 cytoplasmic tail also become phosphorylated, and SHP-2 is recruited to ITSM (also possibly SHP-1). As a consequence, Lck and Zap-70 become dephosphorylated. PD-1 ligation also causes inhibition of PI3K/Akt/mTOR and Ras/MAPK/Erk pathways, leading to downregulation of glycolysis and amino acid metabolism and increase in fatty acid oxidation in T cells. This alteration in T cell metabolic reprograming may change the course of T cell differentiation, leading to impaired differentiation of effector and memory T cells, while enhancing the differentiation of T regulatory cells and exhausted T cells.

Figure 2

Biological and clinical implications of PD-1 ligation on T cell immune function. (A) Engagement of PD-1 by PD-L1 expressed on pathogen-presenting cells inhibits differentiation, activation, and expansion of pathogen-specific T cells in chronic infections. Therapeutic blockade of this pathway can improve pathogen-specific immunity. (B) Engagement of PD-1 by PD-L1 expressed on tissues and APC-presenting self-antigens prevents the generation of self-reactive T effector cells, promotes the differentiation of T_Reg cells, suppresses expansion of escaping self-reactive T cells, and prevents autoimmunity. Therapeutic activation of this pathway may promote transplantation tolerance and induce self-tolerance in autoimmune diseases. (C) Engagement of PD-1 by PD-L1 expressed on cancer cells and immune cells infiltrating the tumor microenvironment (TME) inhibits expansion of tumor-specific T cells, promotes the generation of T_Reg cells, promotes tumor tolerance, and suppresses antitumor immunity. Therapeutic blockade of this pathway can activate antitumor immune responses.

Figure 3

PD-1/PD-L1 blockade enhances tumor rejection by activating T cells. (Left) When PD-1/PD-L1 pathway is active, promotes survival of cancer cells via antiapoptotic signals mediated via PD-L1 and inhibits signaling pathways that lead to activation and expansion of T cells that recognize tumor antigens. Together, these events lead to impaired generation of T effector and memory cells and preferentiation differentiation of T_EX and T_Reg cells, which promote tumor tolerance. (Right) Blocking the PD-1/PD-L1 immune checkpoint pathway by anti-PD-1 or anti-PD-L1 antibodies suppresses cancer cell survival and enhances the antitumor responses of T cells, leading to tumor regression and rejection. In contrast to impaired TCR signaling induced by PD-1 engagement, PD-1/PD-L1 blockade causes activation of T cells by increasing PI3K/Akt or Ras/MAPK pathways, promoting differentiation of effector and memory T cells and suppression of T_EX and T_Reg differentiation.