Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.
Monocytic MDSCs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy.
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DOI：
10.1126/sciadv.adg3736
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发表时间：
2023-06-30
期刊：
影响因子：
13.6
通讯作者：
Yaddanapudi, Kavitha
中科院分区：
文献类型：
--
作者：
Sarkar, Omar S.;Donninger, Howard;Al Rayyan, Numan;Chew, Lewis C.;Stamp, Bryce;Zhang, Xiang;Whitt, Aaron;Li, Chi;Hall, Melissa;Mitchell, Robert A.;Zippelius, Alfred;Eaton, John;Chesney, Jason A.;Yaddanapudi, Kavitha
免疫检查点抑制剂（ICI）治疗对一部分患者的许多癌症有效;很大比例的患者对这种治疗没有反应。ICI抗性的一个促成因素是单核细胞骨髓源性抑制细胞（M-MDSC）的积累，M-MDSC是对T淋巴细胞具有强效免疫抑制活性的先天性免疫细胞的子集。在这里，使用肺癌、黑色素瘤和乳腺癌小鼠模型，我们表明在肿瘤微环境（TME）中表达CD 73的M-MDSC表现出上级T细胞抑制功能。肿瘤来源的PGE 2，一种前列腺素，通过Stat 3和CREB直接诱导M-MDSC中的CD 73表达。由此产生的CD 73过表达诱导腺苷水平升高，腺苷是一种具有T细胞抑制活性的核苷，最终抑制抗肿瘤CD 8 + T细胞活性。TME中的腺苷被重新利用的药物PEG化腺苷脱氨酶（PEG-ADA）消耗增加了CD 8 + T细胞活性并增强了对ICI治疗的反应。因此，PEG-ADA的使用可以成为克服癌症患者对ICI的耐药性的治疗选择。腺苷代谢塑造肿瘤中单核细胞的行为，腺苷的消耗提高癌症治疗的功效。
Immune checkpoint inhibitor (ICI) therapy is effective against many cancers for a subset of patients; a large percentage of patients remain unresponsive to this therapy. One contributing factor to ICI resistance is accumulation of monocytic myeloid-derived suppressor cells (M-MDSCs), a subset of innate immune cells with potent immunosuppressive activity against T lymphocytes. Here, using lung, melanoma, and breast cancer mouse models, we show that CD73-expressing M-MDSCs in the tumor microenvironment (TME) exhibit superior T cell suppressor function. Tumor-derived PGE2, a prostaglandin, directly induces CD73 expression in M-MDSCs via both Stat3 and CREB. The resulting CD73 overexpression induces elevated levels of adenosine, a nucleoside with T cell–suppressive activity, culminating in suppression of antitumor CD8+ T cell activity. Depletion of adenosine in the TME by the repurposed drug PEGylated adenosine deaminase (PEG-ADA) increases CD8+ T cell activity and enhances response to ICI therapy. Use of PEG-ADA can therefore be a therapeutic option to overcome resistance to ICIs in cancer patients. Adenosine metabolism shapes the behavior of monocytes in tumors and depletion of adenosine improves efficacy of cancer therapy.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
32.4
作者：
Chalmin, Fanny;Mignot, Gregoire;Ghiringhelli, Francois
通讯作者：
Ghiringhelli, Francois
影响因子：
4.4
作者：
Li, Qingsheng;Anderson, Charles D.;Egilmez, Nejat K.
通讯作者：
Egilmez, Nejat K.
影响因子：
4.4
作者：
Berg, DJ;Zhang, J;Moore, SA
通讯作者：
Moore, SA
影响因子：
16.6
作者：
Bronte V;Brandau S;Chen SH;Colombo MP;Frey AB;Greten TF;Mandruzzato S;Murray PJ;Ochoa A;Ostrand-Rosenberg S;Rodriguez PC;Sica A;Umansky V;Vonderheide RH;Gabrilovich DI
通讯作者：
Gabrilovich DI