Genome-Wide Screens Reveal Positive and Negative Regulators of PD-L1
MENGWASSER-DOCTOROFMEDICINETHESIS-2020.pdf (12.02Mb)(embargoed until: 2022-05-01)
Mengwasser, Kristen Elizabeth
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CitationMengwasser, Kristen Elizabeth. 2020. Genome-Wide Screens Reveal Positive and Negative Regulators of PD-L1. Doctoral dissertation, Harvard Medical School.
AbstractImmunotherapy through PD-1 checkpoint blockade promotes durable remission in certain subsets of patients, while other tumor subtypes fail to exhibit comparable responses. Among initial responders, patients with disease progression often develop defects in IFNγ signaling. Complete characterization of PD-L1 regulatory pathways and modulators of IFNγ responsiveness may elucidate the mechanisms underlying these discrepancies, as well as expand the utility of these promising treatments. We screened a barcoded ORFeome library for genes that either upregulate PD-L1 or interfere with IFNγ signaling. We found that the CELF family of RNA-binding proteins upregulates PD-L1, in part by stabilizing the PD-L1 mRNA transcript. ANXA2R and GPCRs including LPAR1/2 also increase PD-L1 cell surface expression. Conversely, we showed that SPDYE2, SPDYE4, and SPDYE7P block PD-L1 induction by IFNγ through a JAK-STAT independent mechanism. Finally, we showed that CLK2 and CLK3 inhibit Stat1 phosphorylation, downregulate Stat1, block PD-L1 and disrupt antigen presentation, partially through phosphorylation of PTPN1 and PTPN2. CLK2 is amplified or overexpressed in a large number of immunotherapy-insensitive tumor types; our data suggests that these patients harbor intrinsic resistance to PD-L1 checkpoint blockade. Thus, segregating patients based on CLK2 amplification status or sensitizing tumors to immunotherapy with CLK2 inhibitors may improve clinical responses.
Citable link to this pagehttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365223