CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.
CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.
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DOI：
10.1038/s41388-021-02132-6
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发表时间：
2022-03
期刊：
影响因子：
8
通讯作者：
Singh PK
中科院分区：
文献类型：
--
作者：
King RJ;Shukla SK;He C;Vernucci E;Thakur R;Attri KS;Dasgupta A;Chaika NV;Mulder SE;Abrego J;Murthy D;Gunda V;Pacheco CG;Grandgenett PM;Lazenby AJ;Hollingsworth MA;Yu F;Mehla K;Singh PK
代谢改变调节癌症侵袭性和免疫反应。鉴于胰腺导管腺癌（PDAC）对常规免疫治疗的反应较差，我们研究了代谢改变和免疫抑制之间的联系。我们的代谢酶筛选表明，CD 73（一种产生腺苷的胞外-5 '-核苷酸酶）表达升高与攻击性增加相关。相应地，我们观察到自发性PDAC小鼠模型肿瘤中的间质腺苷水平增加。通过基因操作减少CD 73可消除体内肿瘤生长，并减少PDAC原位小鼠模型中的髓源性抑制细胞（MDSC）。高通量细胞因子分析表明植入CD 73敲除的小鼠中GM-CSF降低。此外，我们注意到在CD 73敲低的胰腺肿瘤中肿瘤内CD 4+和CD 8 + T细胞的IFN-γ表达增加。CD 4 + T细胞的消耗而不是CD 8 + T细胞的消耗消除了减少的CD 73的有益作用。我们还观察到，来自Nt 5e敲低荷瘤小鼠的脾MDSC在离体测定中不能抑制T细胞活化。补充GM-CSF恢复Nt 5e敲除肿瘤中的肿瘤生长，这通过MDSC消耗而恢复。最后，抗CD 73抗体治疗显著改善了吉西他滨在原位模型中的疗效。因此，靶向腺苷轴为改善针对PDAC的抗肿瘤免疫应答提供了新的治疗机会。
Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5’–nucleotidase that generates adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial adenosine levels in tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput cytokine profiling demonstrated decreased GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4+ and CD8+ T cells in pancreatic tumors with CD73 knockdowns. Depletion of CD4+ T cells, but not CD8+ T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing GM-CSF restored tumor growth in Nt5e knockout tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved gemcitabine efficacy in orthotopic models. Thus, targeting the adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC.
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影响因子：
5.6
作者：
Dosch M;Gerber J;Jebbawi F;Beldi G
通讯作者：
Beldi G
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
影响因子：
8.7
作者：
Allard B;Longhi MS;Robson SC;Stagg J
通讯作者：
Stagg J
DOI：
10.1038/nri2938
发表时间：
2011-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1161/atvbaha.111.226837
发表时间：
2012-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Linden J;Cekic C
通讯作者：
Cekic C