Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1

Significance The PD-1/PD-L1 immunoinhibitory axis plays a key role in immune evasion of cancer cells, and therapies targeting PD-1/PD-L1 show high efficacy in certain cancer types. Understanding how cancer drivers regulate immune surveillance will enable development of novel therapeutic strategies targeting cancer-mediated immune evasion, and identification of new biomarkers of response. Here, we utilized genetic screening with a curated library of 500 tumor suppressor genes to identify cohesin subunits and CTCF among the most significant suppressors of PD-L1. We report upregulation of additional key immune-regulatory molecules PD-L2 and MHC-I, and describe transcriptional consequences of loss of the STAG2 cohesin subunit, including an induction of IFN and NF-κB responses, which have implications for biology and treatment of cohesin-deficient tumors.