Detecting New Regulatory Genes For PD-L1

Programmed cell death protein ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) axis has a critical effect on immune suppression in the context of cancer. PD-L1 is expressed on dendritic cells (DCs) and help to prevent immune activation in the absence of danger. In response to interferon signaling, DCs express molecules that play a role in T cell activation such as MHC-II, CD-86, IL12 ect. but in addition, also induce the expression of receptors such as PD-L1 to restrict and control the immune response. In this project we aim to find new genes which regulate PD-L1 expression in cancer cells and primary innate immune cells, compare the regulatory networks between the different cell types and find new targets for therapy.

Preliminary results show IFN betta and LPS have a stimulating effect on bone morrow derived dendritic cells, which alter PD-L1 levels. Lentiviruses containing regulatory genes for PD-L1 (as published in the literature) have been created. We are in the process of preforming genome wide crisper screen to detect additional positive and negative regulatory genes of PD-L1.

While anti-PD-L1 antibody is already in use in the clinic, there is need to acquire a better understanding of the molecular mechanisms that induce these immunosuppressive receptors and find additional targets for therapy. Our genetic approach will lead to finding new genes that play a role in immunosuppression and activation and will shed light on basic biological processes.