UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis

Li, J; Duran, MA; Dhanota, N; Chatila, WK; Bettigole, SE; Kwon, J; Sriram, RK; ... Bakhoum, SF; + view all (2021) Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis. Cancer Discovery , 11 (5) pp. 1212-1227. 10.1158/2159-8290.CD-20-0387. Green open access

[thumbnail of Litchfield_Metastasis and immune evasion from extracellular cGAMP hydrolysis_AAM.pdf]
Preview
Text
Litchfield_Metastasis and immune evasion from extracellular cGAMP hydrolysis_AAM.pdf - Accepted Version

Download (490kB) | Preview

Abstract

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune stimulatory metabolite whose breakdown products include the immune suppressor, adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wildtype ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part, through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway. / Significance: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.

Type: Article
Title: Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/2159-8290.CD-20-0387
Publisher version: https://doi.org/10.1158/2159-8290.CD-20-0387
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10118670
Downloads since deposit
60Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item