Tumor-Derived cGAMP Regulates Activation of the Vasculature

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...

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Veröffentlicht in:Frontiers in immunology 2020-09, Vol.11, p.2090-2090
Hauptverfasser: Campisi, Marco, Sundararaman, Shriram K, Shelton, Sarah E, Knelson, Erik H, Mahadevan, Navin R, Yoshida, Ryohei, Tani, Tetsuo, Ivanova, Elena, Cañadas, 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2020.02090