Figure 1. Interaction of checkpoint proteins and receptors on tumor cells, antigen presenting cells (APCs), T cells and T regulatory cells.
Programmed Death Ligand 1/2 (PD-L1/2), and CD200 are expressed on the tumor cell surface. Soluble CD200 (sCD200) exists in the serum of patients with solid tumors. Binding their ligands on T cells (PD-1, and CD200R, respectively) results in downregulation of the activated T cell immune response. Cytotoxic T lymphocyte Antigen-4 (CTLA-4) on the surface of Tregs and T cells can bind to B7-1/2 on APCs and interfere with T cell activation and proliferation via disruption of the B7-1/2-CD28 costimulatory complex. Indoleamine 2,3-dioxygenase (IDO), an enzyme found in the cytoplasm of tumor cells, catabolizes tryptophan into active metabolites, Kynurenic acid (KYNR), Quinolinic acid (QUIN), 3-Hydroxykynurenine (3-HK) and Picolinic acid (PIC), which contributes to T cell inhibition directly and indirectly through T regulatory cell (Treg) activation. Treg activation results in T cell inhibition through Treg cell surface CTLA-4 and PD-L1/2. The interaction between sCD200, tumor CD200 and Treg CD200R results in Treg activation and further T cell inhibition.