Molecular mechanisms of programmed cell death-1 dependent T cell suppression: relevance for immunotherapy

Abstract

Programmed cell death-1 (PD1) has become a significant target for cancer immunotherapy. PD1 and its receptor programmed cell death 1 ligand 1 (PDL1) are key regulatory physiological immune checkpoints that maintain self-tolerance in the organism by regulating the degree of activation of T and B cells amongst other immune cell types. However, cancer cells take advantage of these immunosuppressive regulatory mechanisms to escape T and B cell-mediated immunity. PD1 engagement on T cells by PDL1 on the surface of cancer cells dramatically interferes with T cell activation and the acquisition of effector capacities. Interestingly, PD1-targeted therapies have demonstrated to be highly effective in rescuing T cell anti-tumor effector functions. Amongst these the use of anti-PD1/PDL1 monoclonal antibodies are particularly efficacious in human therapies. Furthermore, clinical findings with PD1/PDL1 blockers over several cancer types demonstrate clinical benefit. Despite the successful results, the molecular mechanisms by which PD1-targeted therapies rescue T cell functions still remain elusive. Therefore, it is a key issue to uncover the molecular pathways by which these therapies exert its function in T cells. A profound knowledge of PDL1/PD1 mechanisms will surely uncover a new array of targets susceptible of therapeutic intervention. Here, we provide an overview of the molecular events underlying PD1-dependent T cell suppression in cancer.

Keywords: Cancer; immune checkpoint inhibitors; immunotherapy.

Figure 1

Antigen presentation and T cell activation. (A) T cells (right on the picture) get activated through antigen recognition on the surface of antigen presenting cells (APCs) (left of the picture) upon three signals. APCs present antigenic peptides in MHC molecules (pMHC) to T cells through binding to their T cell receptor (TCR). This interaction delivers signal 1 as indicated within the T cell. T cells simultaneously receive additional co-stimulatory and co-inhibitory signals through ligand-receptor interactions within the immunological synapse. On the top, it is represented the CD80-CD28 co-stimulatory interaction, and below two inhibitory interactions between PDL1-PD1 and CD80-CTLA4. The integration of these signals delivers a second signal which drives regulation of T cell activation. A third signal is also provided by cytokine secretion. (B) The figure is represented TCR molecules and associated components which form TCR signalosome. This complex drives T cell activation signaling pathways. TCR signaling initiation depends on LCK activation that phosphorylates TCR-CD3 and CD28 cytoplasmic domains. ZAP70 then binds to CD3ζ and phosphorylates LAT and p38. Phosphorylated LAT recruits other adaptor and signaling molecules as shown which will trigger calcium-dependent and MAPK-dependent pathways. When CD28 associates to CD80 on the surface of the APC, PI3K generates PIP₃ leading to activation of AKT-mTOR pathways which induce T cell proliferation and survival. CD28 engagement also prevents apoptosis and acts synergistically with CD3-dependent signals to ensure correct T cell proliferation, differentiation and growth. In green, adaptor molecules. In red, kinases and in green adaptor molecules.

Figure 2

PD1-dependent inhibitory mechanisms. (A) The figure represents PD1-dependent proximal inhibitory mechanisms, which depend on the recruitment of SHP1 and SHP2 phosphatases. These phosphatases inhibit ZAP70 and PI3K activities (blue arrows). Consequently, downstream intracellular pathways are also terminated, as exemplified in the figure with, AKT, ERK and PKCƟ. (B) Indirect inhibitory mechanisms over TCR signaling and T cell proliferation are shown trigged by the regulation of CK2 expression. The PI3K-dependent signaling pathway activates CDK2 and inhibits SMAD3-depending gene expression as shown. Briefly, PIP₃ activates AKT which enhances ubiquitin ligase SCF^skp2 that degrades the CDK2 inhibitor p27^Kip1. Activated CDK2 triggers cell cycle progression and inactivates SMAD3 by phosphorylation. These pathways are negatively regulated by the PTEN phosphatase that degrades PIP₃. During TCR activation CK2 phosphorylates PTEN with resulting decrease in its activities. When PD1 is engaged PTEN phosphatase activity is active dephosphorylating PIP3, and therefore CK2 expression and activities decrease. (C) Regulation of TCR surface expression by PD1 engagement. PD1 engagement promotes expression of E3 ubiquitin ligases of the CBL family, as shown. These ubiquitin ligases ubiquitylate TCR chains and associated kinases, such as ZAP-70 and PI3K, leading to TRC signaling termination and the removal of TCRs from the T cell surface.

Figure 3

Metabolic consequences of PD1 engagement. PD1 engagement generated a shift on T cell metabolism from glycolysis to β-oxidation by inhibition of ERK and PI3K-AKT activities. PD1-stimulated T cells would then metabolically resemble long-lived memory T cells.