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Campisi M , Sundararaman SK , Shelton SE , Knelson EH , Mahadevan NR , Yoshida R , Tani T , Ivanova E , Canadas I , Osaki T , Lee SWL , Thai T , Han S , Piel BP , Gilhooley S , Paweletz CP , Chiono V , Kamm RD , Kitajima S , Barbie DA
Tumor-Derived cGAMP Regulates Activation of the Vasculature
Front Immunol. 2020 ;11 :2090
PMID: 33013881    PMCID: PMC7507350    URL: https://www.ncbi.nlm.nih.gov/pubmed/33013881
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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.
Notes
Campisi, Marco Sundararaman, Shriram K Shelton, Sarah E Knelson, Erik H Mahadevan, Navin R Yoshida, Ryohei Tani, Tetsuo Ivanova, Elena Canadas, Israel Osaki, Tatsuya Lee, Sharon Wei Ling Thai, Tran Han, Saemi Piel, Brandon P Gilhooley, Sean Paweletz, Cloud P Chiono, Valeria Kamm, Roger D Kitajima, Shunsuke Barbie, David A eng Switzerland Front Immunol. 2020 Sep 4;11:2090. doi: 10.3389/fimmu.2020.02090. eCollection 2020.