TY - JOUR
T1 - Tumor-Derived cGAMP Regulates Activation of the Vasculature
AU - Campisi, Marco
AU - Sundararaman, Shriram K.
AU - Shelton, Sarah E.
AU - Knelson, Erik H.
AU - Mahadevan, Navin R.
AU - Yoshida, Ryohei
AU - Tani, Tetsuo
AU - Ivanova, Elena
AU - Cañadas, Israel
AU - Osaki, Tatsuya
AU - Lee, Sharon Wei Ling
AU - Thai, Tran
AU - Han, Saemi
AU - Piel, Brandon P.
AU - Gilhooley, Sean
AU - Paweletz, Cloud P.
AU - Chiono, Valeria
AU - Kamm, Roger D.
AU - Kitajima, Shunsuke
AU - Barbie, David A.
N1 - Publisher Copyright:
© Copyright © 2020 Campisi, Sundararaman, Shelton, Knelson, Mahadevan, Yoshida, Tani, Ivanova, Cañadas, Osaki, Lee, Thai, Han, Piel, Gilhooley, Paweletz, Chiono, Kamm, Kitajima and Barbie.
PY - 2020/9/4
Y1 - 2020/9/4
N2 - 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.
AB - 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.
KW - Cell Line, Tumor
KW - Coculture Techniques
KW - Endothelial Cells/metabolism
KW - Humans
KW - Lung Neoplasms/blood supply
KW - Neoplasm Proteins/genetics
KW - Neovascularization, Pathologic/genetics
KW - Nucleotides, Cyclic/genetics
KW - Signal Transduction
UR - http://www.scopus.com/inward/record.url?scp=85091454435&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.02090
DO - 10.3389/fimmu.2020.02090
M3 - Article
C2 - 33013881
AN - SCOPUS:85091454435
SN - 1664-3224
VL - 11
SP - 2090
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 2090
ER -
