AUTHOR=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. TITLE=Tumor-Derived cGAMP Regulates Activation of the Vasculature JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02090 DOI=10.3389/fimmu.2020.02090 ISSN=1664-3224 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.