Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.
Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.
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胞外cGAMP水解物的转移和免疫逃避。
DOI：
10.1158/2159-8290.cd-20-0387
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发表时间：
2021-05
期刊：
影响因子：
28.2
通讯作者：
Bakhoum SF
中科院分区：
文献类型：
--
作者：
Li J;Duran MA;Dhanota N;Chatila WK;Bettigole SE;Kwon J;Sriram RK;Humphries MP;Salto-Tellez M;James JA;Hanna MG;Melms JC;Vallabhaneni S;Litchfield K;Usaite I;Biswas D;Bareja R;Li HW;Martin ML;Dorsaint P;Cavallo JA;Li P;Pauli C;Gottesdiener L;DiPardo BJ;Hollmann TJ;Merghoub T;Wen HY;Reis-Filho JS;Riaz N;Su SM;Kalbasi A;Vasan N;Powell SN;Wolchok JD;Elemento O;Swanton C;Shoushtari AN;Parkes EE;Izar B;Bakhoum SF
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 wildtype 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-PD1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune suppressive pathway.
