Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis

Abstract

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS–STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti–PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. Significance: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells. This article is highlighted in the In This Issue feature, p. 995

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

“…Here, we will briefly discuss recent findings that emphasize the role of the cGAS-STING pathway in restricting the anti-tumoral immune response and favoring evasion from immune control. Recently, Li and colleagues demonstrated that the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) promotes metastasis by degrading cGAMP and contributing to the production of adenosine (an immune-suppressive and tumor-promoting metabolite) [ 156 ]. In human cancers, the expression of ENPP1 correlates with lower immune infiltration and resistance to CPIs [ 156 ].…”

“…Recently, Li and colleagues demonstrated that the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) promotes metastasis by degrading cGAMP and contributing to the production of adenosine (an immune-suppressive and tumor-promoting metabolite) [ 156 ]. In human cancers, the expression of ENPP1 correlates with lower immune infiltration and resistance to CPIs [ 156 ]. Additional findings confirm that the cGAS-STING pathway may regulate the immunogenicity of cancer cells.…”

Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

“…However, the immune-activating potential of PARPi may be context-dependent. For example, tumor cells that express the ectonucleotidase ENPP1 degrade extracellular cGAMP, whose breakdown products can be further metabolized to adenosine, an immunosuppressive metabolite, toggling the cGAS-STING pathway from immunostimulatory to immunosuppressive [ 120 ]. Furthermore, PARPi treatment is associated with upregulation of the checkpoint molecule programmed death ligand 1 (PD-L1) [ 121 ].…”

Innate immune signaling drives late cardiac toxicity following DNA damaging cancer therapies

“…Prior reports have revealed that recruitment of cGAS to cytosolic DNA generate cGAS foci 18,19 . Since cGAS-STING-dependent interferon-stimulated genes (ISG) induction following DNA damage was restricted largely to cardiac fibroblasts, we next examined (which was not certified by peer review) is the author/funder.…”