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PD-1/PD-L1
PD-1 or programmed death-1 was first identified and cloned in 1992 as a gene transcriptionally induced upon programmed cell death in T cells. It was subsequently found to be an expressed on activated T, B and myeloid cells, and its cytoplasmic region contains an immunoreceptor tyrosine-based inhibitory motif. PD-1 was a T cell molecule that limited T cell activation and proliferation and promoted tolerance. PD-1 is expressed at low levels by resting T cells and has been shown to be expressed by what some investigators have referred to as “exhausted” T cells in animal models of chronic infection.
In patients with multiple different types of epithelial, hematologic and other malignancies, high levels of PD-1 are detected in circulating and tumor-infiltrating lymphocytes including T cells that are tumor antigen specific, presumably due to chronic antigenic stimulation. These tumor-associated PD-1 expressing effector cells are dysfunctional, and their biological activity can be partially recovered using PD-1 or PD-L1 blocking antibodies. The ligands for the PD-1 receptor are PD-L1 and PD-L2, which are molecules found on antigen-presenting cells, and in the case of PD-L1, it is often expressed on epithelial and other types of tumor cells, resulting in an inhibitory interaction within the tumor microenvironment. The induction of PD-L1 expression by tumor cells may be an adaptive resistance mechanism for tumor cells in response to a developing antitumor immune response. In addition, oncogenic PTEN loss is associated with increased PD-L1 expression in glioma and triple-negative breast cancer cells.
PD-L1 expression can thus also be up-regulated by intrinsic oncogenic pathways as well as interferon-gamma secreted by infiltrating immune cells. PD-L1 and PD-1 are expressed by different cellular components in the tumor microenvironment, where their interaction can inhibit T cell immunity. The engagement of PD-1 by its principal ligand PD-L1 may result in apoptosis in T cells, anergy, “exhaustion”, and secretion of interleukin-10. PD-L1 expression may protect tumor cells expressing it from CD8+T cell-mediated lysis. In addition to PD-1, an interaction between PD-L1 and CD80 has been demonstrated in mouse models. PD-L1 acts as a receptor to “back” transmit signals into T cells and tumor cells to impact on their survival, whose mechanism is yet to be determined. Finally, PD-1 and PD-L1 can be expressed on T regulatory cells and may control their function, and innate immune effectors like NKT cells may also involve the PD-1/PD-L1 circuit.
References
1.Balar AV,et al. Cancer Immunol Immunother. 2017;66(5):551–564.
In patients with multiple different types of epithelial, hematologic and other malignancies, high levels of PD-1 are detected in circulating and tumor-infiltrating lymphocytes including T cells that are tumor antigen specific, presumably due to chronic antigenic stimulation. These tumor-associated PD-1 expressing effector cells are dysfunctional, and their biological activity can be partially recovered using PD-1 or PD-L1 blocking antibodies. The ligands for the PD-1 receptor are PD-L1 and PD-L2, which are molecules found on antigen-presenting cells, and in the case of PD-L1, it is often expressed on epithelial and other types of tumor cells, resulting in an inhibitory interaction within the tumor microenvironment. The induction of PD-L1 expression by tumor cells may be an adaptive resistance mechanism for tumor cells in response to a developing antitumor immune response. In addition, oncogenic PTEN loss is associated with increased PD-L1 expression in glioma and triple-negative breast cancer cells.
PD-L1 expression can thus also be up-regulated by intrinsic oncogenic pathways as well as interferon-gamma secreted by infiltrating immune cells. PD-L1 and PD-1 are expressed by different cellular components in the tumor microenvironment, where their interaction can inhibit T cell immunity. The engagement of PD-1 by its principal ligand PD-L1 may result in apoptosis in T cells, anergy, “exhaustion”, and secretion of interleukin-10. PD-L1 expression may protect tumor cells expressing it from CD8+T cell-mediated lysis. In addition to PD-1, an interaction between PD-L1 and CD80 has been demonstrated in mouse models. PD-L1 acts as a receptor to “back” transmit signals into T cells and tumor cells to impact on their survival, whose mechanism is yet to be determined. Finally, PD-1 and PD-L1 can be expressed on T regulatory cells and may control their function, and innate immune effectors like NKT cells may also involve the PD-1/PD-L1 circuit.
References
1.Balar AV,et al. Cancer Immunol Immunother. 2017;66(5):551–564.