Tumor-Derived cGAMP Regulates Activation of the Vasculature.
2′3′-cGAMP
KRAS
LKB1
STING
T cell
endothelial cells
microfluidic culture
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2020
2020
Historique:
received:
15
06
2020
accepted:
31
07
2020
entrez:
5
10
2020
pubmed:
6
10
2020
medline:
29
4
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33013881
doi: 10.3389/fimmu.2020.02090
pmc: PMC7507350
doi:
Substances chimiques
Neoplasm Proteins
0
Nucleotides, Cyclic
0
cyclic guanosine monophosphate-adenosine monophosphate
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2090Subventions
Organisme : NCI NIH HHS
ID : K00 CA212227
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007627
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA214381
Pays : United States
Informations de copyright
Copyright © 2020 Campisi, Sundararaman, Shelton, Knelson, Mahadevan, Yoshida, Tani, Ivanova, Cañadas, Osaki, Lee, Thai, Han, Piel, Gilhooley, Paweletz, Chiono, Kamm, Kitajima and Barbie.
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