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ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway in breast cancer
Songnan Wang1,2,3, Volker Böhnert1,2, Alby J Joseph1,2,3
1Department of Biochemistry, Stanford University, Stanford, CA 94305.
Abstract:
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer stimulator of interferon genes (STING) pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, we show that ENPP1 in both cancer and normal tissues drives primary breast tumor growth and metastasis by dampening extracellular 2'3'-cyclic-GMP-AMP (cGAMP)-STING-mediated antitumoral immunity. ENPP1 loss-of-function in both cancer cells and normal tissues slowed primary tumor growth and abolished metastasis. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied ENPP1 knockout in a STING-dependent manner, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Finally, ENPP1 expression in breast tumors deterministically predicated whether patients would remain free of distant metastasis after pembrolizumab (anti-PD-1) treatment followed by surgery. Altogether, ENPP1 blockade represents a strategy to exploit cancer-produced extracellular cGAMP for controlled local activation of STING and is therefore a promising therapeutic approach against breast cancer.
Insights
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) dampens anti-tumor immunity by degrading extracellular cyclic GMP-AMP (cGAMP). Inhibiting ENPP1 restores STING pathway activation, slowing breast cancer growth and metastasis.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is linked to poor cancer prognosis.
- ENPP1 hydrolyzes extracellular 2'3'-cyclic-GMP-AMP (cGAMP), an immunotransmitter activating the STING pathway.
- The precise mechanisms of ENPP1's tumorigenic effects are not fully understood.
Purpose of the Study:
- To investigate the role of ENPP1 in breast tumor growth and metastasis.
- To elucidate the molecular and cellular mechanisms by which ENPP1 influences anti-tumor immunity.
- To evaluate ENPP1 blockade as a therapeutic strategy.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) was employed to analyze ENPP1 expression in cancer and normal tissues.
- Loss-of-function studies were conducted to assess the impact of ENPP1 inhibition on tumor growth and metastasis.
- The cGAMP hydrolysis activity of ENPP1 was selectively abolished to determine its specific contribution to anti-cancer effects.
Main Results:
- ENPP1 in both cancer and normal tissues promotes primary breast tumor growth and metastasis.
- ENPP1 dampens STING-mediated anti-tumor immunity by reducing extracellular cGAMP levels.
- Loss of ENPP1 function significantly slowed tumor growth and abolished metastasis.
- Inhibition of ENPP1's cGAMP hydrolysis activity phenocopied ENPP1 knockout, restoring anti-tumor immunity in a STING-dependent manner.
- High ENPP1 expression in breast tumors predicted distant metastasis after pembrolizumab treatment.
Conclusions:
- ENPP1 blockade is a promising therapeutic strategy for breast cancer by restoring anti-tumor immunity.
- Targeting ENPP1 exploits cancer-produced extracellular cGAMP for localized STING activation.
- ENPP1 inhibition offers a novel approach to enhance the efficacy of immunotherapies like pembrolizumab.
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