PD-L1-specific T cells

Abstract

Recently, there has been an increased focus on the immune checkpoint protein PD-1 and its ligand PD-L1 due to the discovery that blocking the PD-1/PD-L1 pathway with monoclonal antibodies elicits striking clinical results in many different malignancies. We have described naturally occurring PD-L1-specific T cells that recognize both PD-L1-expressing immune cells and malignant cells. Thus, PD-L1-specific T cells have the ability to modulate adaptive immune reactions by reacting to regulatory cells. Thus, utilization of PD-L1-derived T cell epitopes may represent an attractive vaccination strategy for targeting the tumor microenvironment and for boosting the clinical effects of additional anticancer immunotherapy. This review summarizes present information about PD-L1 as a T cell antigen, depicts the initial findings about the function of PD-L1-specific T cells in the adjustment of immune responses, and discusses future opportunities.

Keywords: Anti-Tregs; CITIM 2015; Cancer vaccines; PD-L1; PD-L1-specific T cells.

Fig. 1

PD-L1-specific T cells target immune regulatory cells as well as cancer cells. Cancer cells (purple) as well as other regulatory immune cells [e.g., tumor-associated dendritic cells (TADC) (dark red) and MDSC (light red)] express checkpoint inhibitors (e.g., PD-L1), inhibitory cytokines as well as metabolic enzymes that restrain the antitumor activity of anti-tumor-specific T cells (green) in the tumor microenvironment. Specific T cells recognizing HLA-restricted PD-L1-derived epitopes (yellow), which are generated from intracellular degraded PD-L1, are able to eliminate (red arrows) regulatory immune cells as well as cancer cells. Hence, the activation of PD-L1-specific T cells by vaccination may directly target immune inhibitory pathways in the tumor microenvironment, modulate immune regulation, and potentially alter tolerance to tumor antigens. The addition of PD-L1 epitopes to therapeutic cancer vaccines would thus be a simple and highly synergistic means to increase the outcome

Fig. 2

Co-stimulation with PD-L1 epitopes boosts the immunogenicity of a DC-based vaccine. PBMC (numerous colors) was stimulated with an autologous DC-based vaccine (blue) in the presence of IL-2. Subsequently, DC-reactive T cells (green) expand, and this is augmented when PD-L1-specific T cells are activated by co-stimulation with PD-L1-derived epitopes (yellow) assessed in cultures co-stimulated with an HIV control epitope (red)

Fig. 3

A PD-L1 vaccine and checkpoint inhibitors are complimentary. a PD-L1-expressing regulatory immune cells (red) degrade intracellular PD-L1 into peptides (yellow) that are subsequently processed into peptides and presented on the cell surface by HLA molecules, where they are recognized by PD-L1-specific T cells (green). Hence, PD-L1-specific T cells can promote local immune suppression by the secretion of effector cytokines or by killing regulatory immune cells directly (red arrow), thereby influencing general immune reactions. Similarly, they can eliminate PD-L1-expressing malignant cells, b PD-1-positive, PD-L1-specific T cells are themselves hampered by the suppressive effects of PD-L1 expression on their targets and c PD-L1-specific T cells may thus be further boosted by PD-L1 blockade, since PD-L1 mAbs target the same cells as vaccine-induced T cells; this therapeutic strategy will therefore make cells more vulnerable targets. Thus, a PD-L1-based vaccine should be viewed as complementing rather than competing with checkpoint inhibitors