Frontiers in Immunology (Sep 2020)
Tumor-Derived cGAMP Regulates Activation of the Vasculature
- Marco Campisi,
- Marco Campisi,
- Shriram K. Sundararaman,
- Shriram K. Sundararaman,
- Sarah E. Shelton,
- Sarah E. Shelton,
- Erik H. Knelson,
- Navin R. Mahadevan,
- Navin R. Mahadevan,
- Ryohei Yoshida,
- Tetsuo Tani,
- Elena Ivanova,
- Elena Ivanova,
- Israel Cañadas,
- Israel Cañadas,
- Tatsuya Osaki,
- Tatsuya Osaki,
- Sharon Wei Ling Lee,
- Sharon Wei Ling Lee,
- Tran Thai,
- Saemi Han,
- Brandon P. Piel,
- Sean Gilhooley,
- Cloud P. Paweletz,
- Cloud P. Paweletz,
- Valeria Chiono,
- Roger D. Kamm,
- Roger D. Kamm,
- Shunsuke Kitajima,
- Shunsuke Kitajima,
- David A. Barbie,
- David A. Barbie
Affiliations
- Marco Campisi
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
- Marco Campisi
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Shriram K. Sundararaman
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Shriram K. Sundararaman
- University of Virginia School of Medicine, University of Virginia, Charlottesville, VA, United States
- Sarah E. Shelton
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Sarah E. Shelton
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Erik H. Knelson
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Navin R. Mahadevan
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Navin R. Mahadevan
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, United States
- Ryohei Yoshida
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Tetsuo Tani
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Elena Ivanova
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Elena Ivanova
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United States
- Israel Cañadas
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Israel Cañadas
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United States
- Tatsuya Osaki
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Tatsuya Osaki
- Institute of Industrial Science, The University of Tokyo, Tokyo, Japan
- Sharon Wei Ling Lee
- 0Singapore-MIT Alliance for Research & Technology, BioSystems and Micromechanics, Singapore, Singapore
- Sharon Wei Ling Lee
- 1Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Tran Thai
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Saemi Han
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Brandon P. Piel
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Sean Gilhooley
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Cloud P. Paweletz
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Cloud P. Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United States
- Valeria Chiono
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
- Roger D. Kamm
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Roger D. Kamm
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States
- Shunsuke Kitajima
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- Shunsuke Kitajima
- 2Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
- David A. Barbie
- Department of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States
- David A. Barbie
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United States
- DOI
- https://doi.org/10.3389/fimmu.2020.02090
- Journal volume & issue
-
Vol. 11
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.
Keywords
