Tumor-Derived cGAMP Regulates Activation of the Vasculature
Name
fimmu-11-02090.pdf
Description
Published version
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5.13 MB
Format
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Checksum (MD5)
eb683ff32ee1878bd4864a9f66ec6b03
Author(s)
Campisi, Marco
Sundararaman, Shriram K
Shelton, Sarah E
Knelson, Erik H
Mahadevan, Navin R
Yoshida, Ryohei
Tani, Tetsuo
Ivanova, Elena
Cañadas, Israel
Osaki, Tatsuya
Date Issued
September 4, 2020
Journal
Frontiers in Immunology
Publisher
Frontiers Media SA
Citation
Campisi M, Sundararaman SK, Shelton SE, Knelson EH, Mahadevan NR, Yoshida R, Tani T, Ivanova E, Cañadas I, Osaki T, Lee SWL, Thai T, Han S, Piel BP, Gilhooley S, Paweletz CP, Chiono V, Kamm RD, Kitajima S and Barbie DA (2020) Tumor-Derived cGAMP Regulates Activation of the Vasculature. Front. Immunol. 11:2090.
Version
Final published version
Abstract
Intratumoral recruitment of immune cells following innate immune activation is critical for anti-tumor immunity and involves cytosolic dsDNA sensing by the cGAS/STING pathway. We have previously shown that KRAS-LKB1 (KL) mutant lung cancer, which is resistant to PD-1 blockade, exhibits silencing of STING, impaired tumor cell production of immune chemoattractants, and T cell exclusion. Since the vasculature is also a critical gatekeeper of immune cell infiltration into tumors, we developed a novel microfluidic model to study KL tumor-vascular interactions. Notably, dsDNA priming of LKB1-reconstituted tumor cells activates the microvasculature, even when tumor cell STING is deleted. cGAS-driven extracellular export of 2′3′ cGAMP by cancer cells activates STING signaling in endothelial cells and cooperates with type 1 interferon to increase vascular permeability and expression of E selectin, VCAM-1, and ICAM-1 and T cell adhesion to the endothelium. Thus, tumor cell cGAS-STING signaling not only produces T cell chemoattractants, but also primes tumor vasculature for immune cell escape.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Mechanical Engineering
Singapore-MIT Alliance in Research and Technology (SMART)
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.3389/fimmu.2020.02090
