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Zhang JP, Song Z, Wang HB, Lang L, Yang YZ, Xiao W, Webster DE, Wei W, Barta SK, Kadin ME, Staudt LM, Nakagawa M, Yang Y
A novel model of controlling PD-L1 expression in ALK+ Anaplastic Large Cell Lymphoma revealed by CRISPR screening
Blood (2019) 134:171-185.
Abstract
The success of PD1/PD-L1 based immunotherapy highlights the critical role played by PD-L1 in cancer progression, and reveals an urgent need to develop new approaches to attenuate PD-L1 function by gaining insight into how its expression is controlled. ALK positive Anaplastic largecell lymphoma (ALK+ ALCL) expresses a high level of PD-L1 due to the constitutive activation of multiple oncogenic signaling pathways downstream of ALK activity, making it an excellent model in which to define the signaling processes responsible for PD-L1 upregulation in tumor cells. Here, using CRISPR/Cas9 library screening, we sought a comprehensive understanding of the molecular effectors required for PD-L1 regulation in ALK+ ALCL. Indeed, we determined that PD-L1 induction is dependent upon the NPM-ALK oncoprotein activation of STAT3, as well as a signalosome containing GRB2/SOS1 which activates the MEK-ERK and PI3K-AKT signaling pathways. These signaling network through STAT3 and the GRB2/SOS1 ultimately induce PD-L1 expression through the action of transcription factors IRF4 and BATF3 on the enhancer region of the PD-L1 gene. IRF4 and BATF3 are essential for PD-L1 upregulation, and IRF4 expression is correlated with PD-L1 levels in primary ALK+ ALCL tissues. Targeting this oncogenic signaling pathway in ALK+ ALCL largely inhibited the ability of PD-L1 mediated tumor immune escape when co-cultured with PD-1-positive T cells and NK cells. Thus, our identification of this previously unrecognized regulatory hub not only accelerates our understanding of the molecular circuitry that drives tumor immune escape, but also provides novel opportunities to improve immunotherapeutic intervention strategies.
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Publication Date: 2019-07-11.
PMCID: PMC6624970
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Last updated on Monday, November 04, 2019