The Integrated Stress Response Pathway Regulates PD-L1 Translation in Human Lung Cancer

Large-scale sequencing studies have comprehensively identified genomic alterations in human cancers, but they lack the ability to distinguish between cancer driver and passenger mutations. Unbiased genetic screens are a complementary approach for identifying novel cancer driving genes and establishing functional significance of clinically observed mutations. My thesis projects demonstrate how powerful this approach can be in identifying novel therapeutic targets for human cancer treatment. Recent studies have demonstrated that human lung cancer cells express high levels of Programmed Death Ligand 1 (PD-L1), a ligand of the Programmed Death 1 (PD-1) receptor on T-cells, which allows them to directly suppress T-cell proliferation and function. Monoclonal antibodies disrupting this pathway have yielded remarkable clinical results. However, the mechanisms of PD-L1 regulation in tumor cells remain incompletely understood. I used CRISPR-based screening to identify novel regulators of PD-L1 in human lung cancer cells, revealing potent induction of PD-L1 upon disruption of the heme biosynthesis pathway. Impairment of heme production activates the Integrated Stress Response (ISR), allowing bypass of inhibitory upstream open reading frames in the PD-L1 5'UTR, resulting in enhanced PD-L1 translation and immune suppression. I further demonstrated that ISR-dependent translation of PD-L1 requires the translation initiation factor EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is associated with poor prognosis, is sufficient to induce PD-L1. These findings uncover a new mechanism of immune checkpoint activation and suggest novel targets for therapeutic intervention. Additionally, I have also worked on characterizing Steroid Receptor Coactivator-2, previously identified from a forward genetics screen, as a tumor suppressor in MYC-mediated liver tumorigenesis.