Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade

Abstract

Immune checkpoint blockades, such as inhibitors against programmed death 1 (PD-1) and its ligand (PD-L1), have received extensive attention in the past decade because of their dramatic clinical outcomes in advanced malignancies. However, both primary and acquired resistance becomes one of the major obstacles, which greatly limits the long-lasting effects and wide application of PD-1/PD-L1 blockade therapy. PD-1/PD-L1 both regulates and is regulated by cellular signaling pathways and epigenetic modification, thus inhibiting the proliferation and effector function of T and B cells. The lack of tumor antigens and effective antigen presentation, aberrant activation of oncogenic pathways, mutations in IFN-γ signaling, immunosuppressive tumor microenvironment such as regulatory T cells, myeloid-derived suppressor cells, M2 macrophages, and immunoinhibitory cytokines can lead to resistance to PD-1/PD-L1 blockade. In this review, we describe PD-1 related signaling pathways, essential factors contributing to the resistance of PD-1 blockade, and discuss strategies to increase the efficacy of immunotherapy. Furthermore, we discuss the possibility of combined epigenetic therapy with PD-1 blockade as a potential promising approach for cancer treatment.

Extracellular vesicles and their immunomodulatory functions in pregnancy

“…In addition to FasL, TRAIL, and NKG2D ligands, several members of the B7 family of immune-regulatory ligands, which bind to receptors in lymphocytes and mediate immune response, are reported to co-localize with the exosome biosynthetic machinery and released in the exosomes [43,76]. Programmed death ligand-1 (PD-L1) is a member of B7 family of immune-regulatory ligands, expressed on activated immune cells including T cells and has major function in downregulating effector T cell activity and preventing over-stimulation of the immune system [10]. Placental exosomes express PD-L1 and mediate T cell suppression by suppressing the CD3-zeta and JAK3 pathway [76].…”

Molecular T-Cell Repertoire Analysis as Source of Prognostic and Predictive Biomarkers for Checkpoint Blockade Immunotherapy

“…Perhaps the biggest challenge among them is to pass the concept of resistance [29]. The resistance develops in 50% of the patients treated with immunotherapy and consists of a very dynamic and complex mechanism, such as the constitutive expression of PD-L1 on cancer cells, new tumor antigens presentation, epigenetic modifications and modulation of the tumor microenvironment toward a tolerogenic status [30,31]. Hence, a major remaining challenge is identifying which patients The CD28 co-stimulatory receptor, constitutively expressed in 80% of the CD4 + T cells and in 50% of the cytotoxic CD8 + T cells, binds to cognate CD80 and CD86 ligands (also called B7-1 and B7-2, respectively) expressed by APCs.…”

No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis

“…Immune checkpoint blockade therapy improves clinical outcomes in patients with advanced malignancies [1], but a large subset of treated patients do not respond to these agents. The presentation of neoantigens by the major histocompatibility complex (MHC) molecules is a prerequisite for the detection of a tumor cell by the adaptive immune system [2].…”