High-dimensional analysis of the adenosine pathway in high-grade serous ovarian cancer.
High-dimensional analysis of the adenosine pathway in high-grade serous ovarian cancer.
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高级别浆液性卵巢癌腺苷通路的高维分析。
DOI：
10.1136/jitc-2020-001965
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发表时间：
2021-03
影响因子：
10.9
通讯作者：
Stagg J
中科院分区：
文献类型：
--
作者：
Bareche Y;Pommey S;Carneiro M;Buisseret L;Cousineau I;Thebault P;Chrobak P;Communal L;Allard D;Robson SC;Mes-Masson AM;Provencher D;Lapointe R;Stagg J
细胞外ATP水解为腺苷（eADO）是癌症免疫学中重要的免疫检查点。我们在此使用多参数平台研究了eADO通路在高级别浆液性卵巢癌（HGSC）中的影响。我们在大约1200例HGSC患者中对eADO产生的CD39和CD73、eADO信号传导基因特征、免疫基因特征和临床结局进行了转录组学荟萃分析。然后在组织芯片上对大约1000个病例进行CD39、CD73和CD8的蛋白质表达、定位和预后影响，并通过流式细胞术和单细胞RNA测序对一部分患者的肿瘤浸润淋巴细胞（TIL）进行分析。伴随的CD39和CD73基因表达，以及高水平的eADO基因签名，与HGSC患者的预后不良相关，特别是在免疫调节分子亚型中，其特征在于免疫活性微环境。CD39进一步与原发性化学难治性和化学耐药性人HGSC相关，并且基于铂的鼠HGSC化疗在CD39缺陷小鼠中显著更有效。在蛋白质水平，CD39和CD73主要由癌症相关的成纤维细胞表达，并且CD39在严重耗尽、克隆扩增和推定的组织驻留记忆TIL上表达。我们的研究揭示了HGSC中eADO信号传导的临床、免疫学、亚型特异性影响，揭示了CD39的化学保护作用，并支持在卵巢癌患者中评价eADO靶向药物。
Hydrolysis of extracellular ATP to adenosine (eADO) is an important immune checkpoint in cancer immunology. We here investigated the impact of the eADO pathway in high-grade serous ovarian cancer (HGSC) using multiparametric platforms. We performed a transcriptomic meta-analysis of eADO-producing CD39 and CD73, an eADO signaling gene signature, immune gene signatures and clinical outcomes in approximately 1200 patients with HGSC. Protein expression, localization and prognostic impact of CD39, CD73 and CD8 were then performed on approximately 1000 cases on tissue microarray, and tumor-infiltrating lymphocytes (TILs) were analyzed by flow cytometry and single-cell RNA sequencing on a subset of patients. Concomitant CD39 and CD73 gene expression, as well as high levels of an eADO gene signature, were associated with worse prognosis in patients with HGSC, notably in the immunoregulatory molecular subtype, characterized by an immune-active microenvironment. CD39 was further associated with primary chemorefractory and chemoresistant human HGSC and platinum-based chemotherapy of murine HGSC was significantly more effective in CD39-deficient mice. At protein level, CD39 and CD73 were predominantly expressed by cancer-associated fibroblasts, and CD39 was expressed on severely exhausted, clonally expanded and putative tissue-resident memory TILs. Our study revealed the clinical, immunological, subtype-specific impacts of eADO signaling in HGSC, unveiled the chemoprotective effect of CD39 and supports the evaluation of eADO-targeting agents in patients with ovarian cancer.
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影响因子：
3.8
作者：
Le Page C;Rahimi K;Köbel M;Tonin PN;Meunier L;Portelance L;Bernard M;Nelson BH;Bernardini MQ;Bartlett JMS;Bachvarov D;Gotlieb WH;Gilks B;McAlpine JN;Nachtigal MW;Piché A;Watson PH;Vanderhyden B;Huntsman DG;Provencher DM;Mes-Masson AM
通讯作者：
Mes-Masson AM
影响因子：
7.2
作者：
d'Almeida, Senan M.;Kauffenstein, Gilles;Tabiasco, Julie
通讯作者：
Tabiasco, Julie
影响因子：
7.7
作者：
Kothari S;Phan JH;Stokes TH;Osunkoya AO;Young AN;Wang MD
通讯作者：
Wang MD
影响因子：
32.4
作者：
Borges da Silva H;Peng C;Wang H;Wanhainen KM;Ma C;Lopez S;Khoruts A;Zhang N;Jameson SC
通讯作者：
Jameson SC
DOI：
10.1158/1078-0432.ccr-18-0784
发表时间：
2018-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chen GM;Kannan L;Geistlinger L;Kofia V;Safikhani Z;Gendoo DMA;Parmigiani G;Birrer M;Haibe-Kains B;Waldron L
通讯作者：
Waldron L