Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

Abstract

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

Immune Checkpoint Inhibitor Therapy Induces Inflammatory Activity in the Large Arteries of Lymphoma Patients under 50 Years of Age

“…The underlying mechanism of inflammatory activation by ICI treatment, however, remains unclear. Pioneering studies have demonstrated that PD-L1 is expressed on endothelial cells and antigen-presenting cells (such as dendritic cells or macrophages) in the vasculature, whereas PD-1 is expressed on activated T-cells [ 12 , 13 ]. The protective immunity of vascular PD-L1 and T-cell PD-1 interaction downregulates the T-cell activation coupled with subsequent apoptosis or the suppression of cluster of differentiation 4 (CD4+) and CD8+ T-cell proliferation [ 13 ].…”

“…In line with our hypothesis, this could be related to previous increases in effector-memory CD4+ T-cells in these inflamed arterial segments [ 14 ]. In summary, the vascular PD-L1 and PD-1 axes could exert an atheroprotective mechanism to maintain peripheral immune tolerance, and an intercepted PD-1/PD-L1 axis between PD-1 high T-cells and PD-L1 high endothelium/macrophages could destruct vascular integrity [ 12 , 15 ]. PD-1 deficiency or inhibition of the T-cells could accelerate intimal infiltration of CD8+ T-cells without directly affecting the myeloid system, according with our findings regarding non-statistical significance changes in the uptake of spleen and bone marrow [ 14 ].…”

Combination therapy with immune checkpoint inhibitors (ICIs); a new frontier

“…The cytoplasmic tail of PD-1 includes two tyrosine-based structural motifs, an immunoreceptor tyrosine-based inhibitory motif (ITIM) (V/L/I/XpYXX/L/V) and an immunoreceptor tyrosine-based switch motif (ITSM) (TXpYXXV/I) [ 65 ]. The PD-1 suppressive activities depend on the ITSM phosphotyrosine, which in turn, potentiates the recruiting SHP-2 and suppressing downstream signaling pathways like CTL-4 [ 65 , 66 ]. Various tumors apply this mechanism by up-regulation of PD-L1 which often relates to unfavorable prognosis.…”

Perspectives on Vascular Regulation of Mechanisms Controlling Selective Immune Cell Function in the Tumor Immune Response

“…Immune checkpoint proteins such as programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are important regulators of the immune response and treatment with inhibitors of these has been proven effective in treatment of certain cancers [5]. Inflammation increases EC PD-L1 expression [67][68][69] with consequences for the tumor immune response, thus suppressing the T cell response. The efficacy of immune checkpoint inhibition is commonly increased by simultaneous anti-angiogenic treatment [68,70].…”