Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity

Jacqueline A Carozza; Volker Böhnert; Khanh C Nguyen; Gemini Skariah; Kelsey E Shaw; Jenifer A Brown; Marjan Rafat; Rie von Eyben; Edward E Graves; Jeffrey S Glenn; Mark Smith; Lingyin Li

doi:10.1038/s43018-020-0028-4

Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity

Nat Cancer. 2020 Feb;1(2):184-196. doi: 10.1038/s43018-020-0028-4. Epub 2020 Feb 24.

Authors

Jacqueline A Carozza^#^{1

2}, Volker Böhnert^#^{2

3}, Khanh C Nguyen⁴, Gemini Skariah^{2

3}, Kelsey E Shaw^{2

3}, Jenifer A Brown^{2

5}, Marjan Rafat⁶, Rie von Eyben⁶, Edward E Graves⁶, Jeffrey S Glenn⁴, Mark Smith², Lingyin Li^{7

8}

Affiliations

¹ Department of Chemistry, Stanford University, Stanford, CA, USA.
² Stanford ChEM-H, Stanford University, Stanford, CA, USA.
³ Department of Biochemistry, Stanford University, School of Medicine, Stanford, CA, USA.
⁴ Departments of Medicine and Microbiology & Immunology, Stanford University, School of Medicine, Stanford, CA, USA.
⁵ Biophysics Program, Stanford University, Stanford, CA, USA.
⁶ Department of Radiation Oncology, Stanford University, School of Medicine, Stanford, CA, USA.
⁷ Stanford ChEM-H, Stanford University, Stanford, CA, USA. lingyinl@stanford.edu.
⁸ Department of Biochemistry, Stanford University, School of Medicine, Stanford, CA, USA. lingyinl@stanford.edu.

^# Contributed equally.

Abstract

2'3'-cyclic GMP-AMP (cGAMP) is an intracellular second messenger that is synthesized in response to cytosolic double-stranded DNA and activates the innate immune STING pathway. Our previous discovery of its extracellular hydrolase ENPP1 hinted at the existence of extracellular cGAMP. Here, we detected that cGAMP is continuously exported but then efficiently cleared by ENPP1, explaining why it has previously escaped detection. By developing potent, specific, and cell impermeable ENPP1 inhibitors, we found that cancer cells continuously export cGAMP in culture at steady state and at higher levels when treated with ionizing radiation (IR). In mouse tumors, depletion of extracellular cGAMP decreased tumor-associated immune cell infiltration and abolished the curative effect of IR. Boosting extracellular cGAMP with ENPP1 inhibitors synergized with IR to delay tumor growth. In conclusion, extracellular cGAMP is an anti-cancer immunotransmitter that could be harnessed to treat cancers with low immunogenicity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Mice
Neoplasms* / radiotherapy
Nucleotides, Cyclic* / genetics
Second Messenger Systems

Substances

Nucleotides, Cyclic
cyclic guanosine monophosphate-adenosine monophosphate

Abstract

Publication types

MeSH terms

Substances

Grants and funding