CD73 Inhibits cGAS-STING and Cooperates with CD39 to Promote Pancreatic Cancer.
CD73 Inhibits cGAS-STING and Cooperates with CD39 to Promote Pancreatic Cancer.
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DOI：
10.1158/2326-6066.cir-22-0260
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发表时间：
2023-01-03
影响因子：
10.1
通讯作者：
中科院分区：
文献类型：
--
作者：
外核苷酶CD39和CD73催化细胞外三磷酸腺苷（ATP）转化为免疫抑制腺苷（ADO），因此代表了潜在的癌症靶点。我们通过临床样本和实验小鼠肿瘤研究CD39和CD73在胰腺导管腺癌（PDAC）中的生物学影响。在人类PDAC样本中，基质CD39和肿瘤CD73的表达与较差的生存率显著相关，并消除了与肿瘤浸润性CD8+ T细胞存在相关的有利预后影响。在小鼠移植的KPC肿瘤中，骨髓细胞上的CD39和CD73以及肿瘤细胞上的CD73均可促进浸润性骨髓细胞向m2样表型极化，从而促进肿瘤生长。肿瘤特异性CD8+ T细胞和胰腺星状细胞上的CD39也抑制T细胞产生IFNγ。虽然治疗性抑制CD39或CD73在体内显著延缓肿瘤生长，但靶向这两种外核苷酶显示出明显更好的抗肿瘤活性。CD73在人和小鼠PDAC肿瘤细胞上的表达也对吉西他滨和辐照诱导的DNA损伤具有保护作用。因此，人类PDAC细胞系的大规模药物基因组学分析揭示了CD73表达与吉西他滨化疗耐药之间的显著关联。引人注目的是，cd73缺陷肿瘤细胞中DNA损伤的增加与cGAS-STING通路的激活有关。此外，CD73抑制剂AB680的体内抗肿瘤活性需要cGAS在小鼠KPC肿瘤细胞中的表达。因此，我们的研究阐明了CD73和CD39似乎合作促进PDAC进展的分子机制。
The ectonucleotidases CD39 and CD73 catalyze extracellular adenosine triphosphate (ATP) to immunosuppressive adenosine (ADO), and as such, represent potential cancer targets. We investigated biological impacts of CD39 and CD73 in pancreatic ductal adenocarcinoma (PDAC) by studying clinical samples and experimental mouse tumors. Stromal CD39 and tumoral CD73 expression significantly associated with worse survival in human PDAC samples and abolished the favorable prognostic impact associated with the presence of tumor-infiltrating CD8+ T cells. In mouse transplanted KPC tumors, both CD39 and CD73 on myeloid cells, as well as CD73 on tumor cells, promoted polarization of infiltrating myeloid cells towards an M2-like phenotype, which enhanced tumor growth. CD39 on tumor-specific CD8+ T cells and pancreatic stellate cells also suppressed IFNγ production by T cells. Although therapeutic inhibition of CD39 or CD73 alone significantly delayed tumor growth in vivo, targeting of both ectonucleotidases exhibited markedly superior anti-tumor activity. CD73 expression on human and mouse PDAC tumor cells also protected against DNA damage induced by gemcitabine and irradiation. Accordingly, large-scale pharmacogenomic analyses of human PDAC cell lines revealed significant associations between CD73 expression and gemcitabine chemoresistance. Strikingly, increased DNA damage in CD73-deficient tumor cells associated with activation of the cGAS-STING pathway. Moreover, cGAS expression in mouse KPC tumor cells was required for anti-tumor activity of the CD73 inhibitor AB680 in vivo. Our study, thus, illuminates molecular mechanisms whereby CD73 and CD39 seemingly cooperate to promote PDAC progression.
影响因子：
37.3
作者：
Rust S;Guillard S;Sachsenmeier K;Hay C;Davidson M;Karlsson A;Karlsson R;Brand E;Lowne D;Elvin J;Flynn M;Kurosawa G;Hollingsworth R;Jermutus L;Minter R
通讯作者：
Minter R