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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-09-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.02090/full |
| id |
doaj-348d85a40f0943e896d94e5eb485e66c |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Tumor-Derived cGAMP Regulates Activation of the Vasculature Frontiers in Immunology LKB1 2′3′-cGAMP STING KRAS T cell endothelial cells |
| author_facet |
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 |
| author_sort |
Marco Campisi |
| title |
Tumor-Derived cGAMP Regulates Activation of the Vasculature |
| title_short |
Tumor-Derived cGAMP Regulates Activation of the Vasculature |
| title_full |
Tumor-Derived cGAMP Regulates Activation of the Vasculature |
| title_fullStr |
Tumor-Derived cGAMP Regulates Activation of the Vasculature |
| title_full_unstemmed |
Tumor-Derived cGAMP Regulates Activation of the Vasculature |
| title_sort |
tumor-derived cgamp regulates activation of the vasculature |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2020-09-01 |
| description |
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. |
| topic |
LKB1 2′3′-cGAMP STING KRAS T cell endothelial cells |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.02090/full |
| work_keys_str_mv |
AT marcocampisi tumorderivedcgampregulatesactivationofthevasculature AT marcocampisi tumorderivedcgampregulatesactivationofthevasculature AT shriramksundararaman tumorderivedcgampregulatesactivationofthevasculature AT shriramksundararaman tumorderivedcgampregulatesactivationofthevasculature AT saraheshelton tumorderivedcgampregulatesactivationofthevasculature AT saraheshelton tumorderivedcgampregulatesactivationofthevasculature AT erikhknelson tumorderivedcgampregulatesactivationofthevasculature AT navinrmahadevan tumorderivedcgampregulatesactivationofthevasculature AT navinrmahadevan tumorderivedcgampregulatesactivationofthevasculature AT ryoheiyoshida tumorderivedcgampregulatesactivationofthevasculature AT tetsuotani tumorderivedcgampregulatesactivationofthevasculature AT elenaivanova tumorderivedcgampregulatesactivationofthevasculature AT elenaivanova tumorderivedcgampregulatesactivationofthevasculature AT israelcanadas tumorderivedcgampregulatesactivationofthevasculature AT israelcanadas tumorderivedcgampregulatesactivationofthevasculature AT tatsuyaosaki tumorderivedcgampregulatesactivationofthevasculature AT tatsuyaosaki tumorderivedcgampregulatesactivationofthevasculature AT sharonweilinglee tumorderivedcgampregulatesactivationofthevasculature AT sharonweilinglee tumorderivedcgampregulatesactivationofthevasculature AT tranthai tumorderivedcgampregulatesactivationofthevasculature AT saemihan tumorderivedcgampregulatesactivationofthevasculature AT brandonppiel tumorderivedcgampregulatesactivationofthevasculature AT seangilhooley tumorderivedcgampregulatesactivationofthevasculature AT cloudppaweletz tumorderivedcgampregulatesactivationofthevasculature AT cloudppaweletz tumorderivedcgampregulatesactivationofthevasculature AT valeriachiono tumorderivedcgampregulatesactivationofthevasculature AT rogerdkamm tumorderivedcgampregulatesactivationofthevasculature AT rogerdkamm tumorderivedcgampregulatesactivationofthevasculature AT shunsukekitajima tumorderivedcgampregulatesactivationofthevasculature AT shunsukekitajima tumorderivedcgampregulatesactivationofthevasculature AT davidabarbie tumorderivedcgampregulatesactivationofthevasculature AT davidabarbie tumorderivedcgampregulatesactivationofthevasculature |
| _version_ |
1724503318725656576 |
| spelling |
doaj-348d85a40f0943e896d94e5eb485e66c2020-11-25T03:47:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-09-011110.3389/fimmu.2020.02090572964Tumor-Derived cGAMP Regulates Activation of the VasculatureMarco Campisi0Marco Campisi1Shriram K. Sundararaman2Shriram K. Sundararaman3Sarah E. Shelton4Sarah E. Shelton5Erik H. Knelson6Navin R. Mahadevan7Navin R. Mahadevan8Ryohei Yoshida9Tetsuo Tani10Elena Ivanova11Elena Ivanova12Israel Cañadas13Israel Cañadas14Tatsuya Osaki15Tatsuya Osaki16Sharon Wei Ling Lee17Sharon Wei Ling Lee18Tran Thai19Saemi Han20Brandon P. Piel21Sean Gilhooley22Cloud P. Paweletz23Cloud P. Paweletz24Valeria Chiono25Roger D. Kamm26Roger D. Kamm27Shunsuke Kitajima28Shunsuke Kitajima29David A. Barbie30David A. Barbie31Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, ItalyDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesUniversity of Virginia School of Medicine, University of Virginia, Charlottesville, VA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesBelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesBlood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, United StatesDepartment of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesInstitute of Industrial Science, The University of Tokyo, Tokyo, Japan0Singapore-MIT Alliance for Research & Technology, BioSystems and Micromechanics, Singapore, Singapore1Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesBelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United StatesDepartment of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, ItalyDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, United StatesDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United States2Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, JapanDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA, United StatesBelfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, United StatesIntratumoral 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.02090/fullLKB12′3′-cGAMPSTINGKRAST cellendothelial cells |