PD-L1

PD-L1 checkpoint is operative in peripheral tissues and serves as a negative regulator of T-cells to help control local inflammatory responses and maintain self-tolerance. It is constitutively expressed on a subset of macrophages, but may be rapidly upregulated in a number of different tissue types and by tumors in response to interferon-gamma and other inflammatory mediators.

Many tumor cells constitutively express or are induced by interferon-γ (IFNγ) to express the inhibitory molecule PDL1. Additionally, loss of the tumor suppressor gene phosphatase and tensin homolog (PTEN) increases tumor cell expression of PDL1. PDL1 was the third member of the B7 family to be identified and exhibited distinct functional characteristics as compared to costimulatory molecules CD80 and CD86. In addition to being expressed on tumor cells, PDL1 is expressed on T and B cells, dendritic cells, macrophages, MDSC, and Tregs, contributing to their suppressive activity. PDL1 suppresses anti-tumor immunity by binding to its receptor, programmed death-1 (PD1, CD279) on activated T cells, resulting in the apoptotic death of activated T cells. In the context of cancer, T cell inhibition through PD1 is unfavorable; however in the absence of cancer, PD1 is crucial for maintaining immune tolerance. Mice lacking the PD1 gene have a higher prevalence of autoimmune disease. Moreover, blockade of PD1 or knocking out the gene in mice leads to accelerated autoimmune disease.

In the tumor microenvironment, tumor-associated PDL1 increases T cell apoptosis. Experiments comparing mock transfected 624mel cutaneous melanoma cells (624mel/mock) or PDL1-transfected 624mel (624mel/PDL1) cocultured with activated T cells identified that 624mel/PDL1 caused an increased prevalence of T cell-apoptotic death as compared to 624mel/mock. In agreement with tumor cell-expressed PDL1 causing apoptotic death of T cells, the use of blocking PDL1 monoclonal antibodies (mAb) decreased T cell death by >50%. Similar observations were seen in vivo, confirming the role of PD1-PDL1-mediated immunosuppression.

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