Drug Related Induction of PD-L1 in Cancer Cells
Student: Davis Graham ’22
Research Mentors: Bert O’Malley, David Lonard, and Yosi Gilad (Baylor College of Medicine Department of Molecular and Cellular Biology)
Cancer cells frequently utilize a variety of mechanisms to evade the immune system of their host and some cancer drugs can actually contribute to the activation of these mechanisms. Normal cells need to be able to use these mechanisms to avoid the immune system of their host. A gene of interest was validated in lung cancer cells as a gene involved in cancer cell’s drug related immune evasion ability, but that is not involved in a normal cell’s immune evasion ability.
Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD1) comprise the PD-L1 immune checkpoint ligand-receptor axis. PD-L1 ligand binding to its receptor (PD1) restrains the immunogenic response and under normal conditions the PD-L1 axis is responsible for maintaining immune homeostasis and preventing autoimmunity. Cancer cells can upregulate the expression of PD-L1 due to drug treatment, supposably as an escape program triggered by pharmacological pressure. Interferon-gamma (IFN-γ) is a physiological inducer of PD-L1, which can act to balance an immune response.
The PD-L1 axis is targeted for treating cancer to unleash the immune system so it can resume its anticancer activity. Targeting immune checkpoints in cancer can result in severe autoimmune-like effects in patients. We explored whether inhibition of specific molecular targets will suppress the induction of PD-L1 under drug pressure while preserving its IFN-γ induced expression.
The Cancer Genome Atlas (TCGA) was used to identify AXL, FOSL1, and NT5E as genes that correlated with CD274 (PD-L1) mRNA expression without major links to IFN-γ related pathways. We hypothesize these genes might be involved in a non-canonical pathway of PD-L1 induction. Due to the availability of a small molecule AXL inhibitor, we chose this gene to test our hypothesis.
To test drug-related induction of PD-L1 we used Paclitaxel (PTX) and Gemcitabine (GEM) — known PD-L1 inducing chemotherapies. The inducibility of PD-L1 under physiological-like and pharmacological conditions was confirmed via qPCR and Western blot. Next, we subjected the cells to AXL inhibiton, followed by IFN-γ or PTX treatments. PD-L1 expression was then tracked by qPCR.
AXL inhibition reduced drug-related PD-L1 induction while keeping IFN-γ induced expression intact. The data indicated AXL is involved in a non-canonical pathway of PD-L1 induction and combinations of a PD-L1 inhibitor and other agents may provide future therapeutic benefit.