Programmed death-1 & its ligands: promising targets for cancer immunotherapy

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From: Immunotherapy(Vol. 7, Issue 7)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 13,124 words
Lexile Measure: 2060L

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Author(s): Rajeev K Shrimali aff1 , John E Janik aff1 , Rasha Abu-Eid aff1 , Mikayel Mkrtichyan aff1 , Samir N Khleif [*] aff1

Keywords:

combination cancer immunotherapy; immune escape; immune inhibitory pathway; PD-1 receptor; PD-ligands; PD-L1

Immune surveillance under normal conditions provides a perfect balance between the prevention of an autoimmune attack and elimination of tumor development [1 ]. This balance is well regulated by an array of costimulatory receptor/ligand pairs, such as glucocorticoid-induced TNF receptor (GITR)/GITR ligand, OX40/OX40 ligand and 4-1BB/4-1BB ligand or immune inhibitory receptor/ligand pairs, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4)/CD80/86, programmed death-1 (PD-1)/PD-L1/L2, T-cell immunoglobulin and mucin domain-3 (TIM-3)/galectin-9 and lymphocyte activation gene-3 (LAG-3)/MHC II. These costimulatory and immune inhibitory receptor/ligand pairs are collectively known as immune checkpoints [2-4 ]. Immune inhibitors such as CTLA-4 (CD152) and PD-1 (CD279) play an important role in avoiding detrimental self-tissue destruction that can lead to autoimmunity. These immune inhibitors are upregulated on activated immune cells and can directly suppress autoreactive T cells or work indirectly by enabling various immune suppressive cells including T-regulatory cells (Tregs) to put a brake on autoimmunity [5,6 ]. These immune inhibitors are essential not only during hyperactive immune conditions such as autoimmunity, inflammation and organ transplants but also during normal biological conditions such as embryo implantation and development [6,7 ]. Reinvigorating the immune attack on tumor cells by suppressing the inhibitory pathway, which leads to the breaking of self-immune tolerance, is central to the success of cancer immunotherapy [4,8,9 ]. Inflammatory conditions during tumor development and progression upregulate many of these immune inhibitory receptors on tumor infiltrating immune cells. At the same time, cancer cells and other antigen-presenting cells (APCs), including immature dendritic cells or macrophages in the inflamed tumor milieu, overexpress these ligands [10,11 ].

CTLA-4 and PD-1, the two most important immune inhibitory receptors with respect to their clinical success, exhibit different sites and schedules of inhibitory activity that correlate to their activation stage following antigenic stimulation. CTLA-4 is upregulated immediately upon initiation of T-cell receptor (TCR) stimulation, while PD-1 is a late activation marker and expressed only on activated T cells [12,13 ]. Binding of CTLA-4 to its ligands B7.1 and B7.2 (CD80 and CD86, respectively) on APCs occurs in central lymphoid organs such as lymph nodes, activating the CTLA-4-mediated inhibitory pathway, which blocks the early activation and expansion of T cells. On the other hand, PD-1, present on activated T cells, binds to its ligands PD-L1 and PD-L2 primarily in the periphery, for example, in the tumor site, activating the PD-1 inhibitory pathway, which suppresses T-cell proliferation and induces downregulation of T-cell effector function and apoptosis [12-15 ]. Many tumors use the PD-1/PD-L1 interaction as a major immune escape mechanism to avoid detection and elimination by cell-mediated immunity [ 15,16 ]. Not surprisingly, significant advances made in terms of achieving clinical efficacy by targeting the PD-1 pathway makes this receptor ligand a candidate of prime interest for cancer immunotherapy. In fact, PD-1 (CD279) and its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273) are...

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Gale Document Number: GALE|A428994457