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Park, Sung Ho
Laboratory of Molecular Immunology
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VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers

Author(s)
Kim, Chang GonJang, MiKim, YoungunLeem, GalamKim, Kyung HwanLee, HoyoungKim, Tae-ShinChoi, Seong JinKim, Hyung-DonHan, Ji WonKwon, MinsukKim, Jong HoonLee, Andrew J.Nam, Su KyungBae, Seok-JooLee, Sat ByolShin, Sang JoonPark, Sung HoAhn, Joong BaeJung, InkyungLee, Kang YoungPark, Su HyungKim, HoguenMin, Byung SohShin, Eui-Cheol
Issued Date
2019-11
DOI
10.1126/sciimmunol.aay0555
URI
https://scholarworks.unist.ac.kr/handle/201301/30960
Fulltext
https://immunology.sciencemag.org/content/4/41/eaay0555
Citation
SCIENCE IMMUNOLOGY, v.4, no.41, pp.eaay0555
Abstract
Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade-resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.
Publisher
American Association for the Advancement of Science
ISSN
2470-9468
Keyword
IMMUNE-CHECKPOINT BLOCKADEENDOTHELIAL GROWTH-FACTORINHIBITORY RECEPTOR PD-1ANTI-PD-1 ANTIBODYSOLID TUMORSOPEN-LABELPHASE-IEXPRESSIONNIVOLUMABRESISTANCE

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