Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.
Expression of B7-H4 and IDO1 is associated with drug resistance and poor prognosis in high-grade serous ovarian carcinomas.
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B7-H4和IDO1的表达与耐药性和预后不良有关。
DOI：
10.1016/j.humpath.2021.04.003
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发表时间：
2021-07
期刊：
影响因子：
3.3
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Niu N;Shen W;Zhong Y;Bast RC Jr;Jazaeri A;Sood AK;Liu J
高级别浆液性卵巢癌(HGSC)是最致命的妇科恶性肿瘤。虽然针对PD-L1和CTLA-4的免疫检查点抑制剂在多种肿瘤类型中显示出显著的效果，但在HGSC中对单剂免疫检查点抑制剂的应答率很低。必须确定替代的生物标志物和靶点，以指导HGSC患者的选择和新的治疗策略。在这里，我们旨在探讨新型免疫调节剂，包括B7-H4、IDO1、TIM3、IL6和IL-8在HGSC患者中的临床意义。我们初步分析了48例HGSCs患者，其中24例对标准紫杉醇和卡铂化疗敏感，24例对标准紫杉醇和卡铂耐药。用包含33个免疫相关基因的纳米串分析比较不同免疫调节分子在敏感和耐药组中的表达。对在MDACC接受初次手术的202名HGSCs患者的组织阵列进行多重免疫组织化学染色，验证差异表达的蛋白。我们分析了免疫检查点的表达水平，并将表达谱与临床病理特征进行比较，包括应答、无进展生存期和总生存期。耐药HGSC中B7-H4(69.3%)、IDO1(71.8%)、TIM3(89.1%)及炎性因子IL-6、IL-8在间质成分中高表达，TIM3高表达。B7-H4和IDO1的高表达与总体生存率和无进展生存率显著降低相关。49.1%的病例同时表达B7-H4和IDO1。HGSC高水平表达一组免疫调节蛋白，包括B7-H4、IDO1、TIM3、IL-6和IL-8。这些调节剂代表了加强HGSC患者免疫治疗的新靶点。
High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy. While immune checkpoint inhibitors against PD-L1 and CTLA-4 have shown significant effects in multiple tumor types, the response rate to single-agent immune checkpoint inhibitors is low in HGSC. Alternative biomarkers and targets must be identified to guide patient selection and new therapeutic strategies in HGSC. Here, we aim to investigate the clinical significance of novel immune modulators, including B7-H4, IDO1, Tim3, IL6, and IL-8, in patients with HGSC. A total of 48 patients with HGSCs, comprising 24 cases that were sensitive and 24 that were resistant to standard paclitaxel and carboplatin chemotherapy, were selected for our initial analysis. A NanoString assay including 33 immune-related genes was used to compare the expression of different immune regulatory molecules in the sensitive and resistant groups. Differentially expressed proteins were verified using multiplex immunohistochemical staining on tissue arrays of 202 patients with HGSCs who underwent primary surgery at MDACC. We analyzed the expression levels of immune checkpoints and compared expression profiles with clinicopathologic features including response, progression-free survival, and overall survival. HGSC tumors resistant to therapy expressed higher levels of B7-H4 (69.3%), IDO1 (71.8%), Tim3 (89.1%) and inflammatory factors IL-6 and IL-8 and expressed higher Tim3 in stromal components. High expression of B7-H4 and IDO1 was associated with significantly lower overall survival and progression-free survival. B7-H4 and IDO1 were co-expressed in 49.1% of studied cases. A panel of immunomodulatory proteins including B7-H4, IDO1, Tim3, IL-6, and IL-8 are expressed at high levels in HGSCs. These modulators represent novel targets to enhance immunotherapy in patients with HGSCs.
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影响因子：
7.4
作者：
Galon J;Pagès F;Marincola FM;Angell HK;Thurin M;Lugli A;Zlobec I;Berger A;Bifulco C;Botti G;Tatangelo F;Britten CM;Kreiter S;Chouchane L;Delrio P;Arndt H;Asslaber M;Maio M;Masucci GV;Mihm M;Vidal-Vanaclocha F;Allison JP;Gnjatic S;Hakansson L;Huber C;Singh-Jasuja H;Ottensmeier C;Zwierzina H;Laghi L;Grizzi F;Ohashi PS;Shaw PA;Clarke BA;Wouters BG;Kawakami Y;Hazama S;Okuno K;Wang E;O'Donnell-Tormey J;Lagorce C;Pawelec G;Nishimura MI;Hawkins R;Lapointe R;Lundqvist A;Khleif SN;Ogino S;Gibbs P;Waring P;Sato N;Torigoe T;Itoh K;Patel PS;Shukla SN;Palmqvist R;Nagtegaal ID;Wang Y;D'Arrigo C;Kopetz S;Sinicrope FA;Trinchieri G;Gajewski TF;Ascierto PA;Fox BA
通讯作者：
Fox BA
影响因子：
11.2
作者：
Hartman ZC;Poage GM;den Hollander P;Tsimelzon A;Hill J;Panupinthu N;Zhang Y;Mazumdar A;Hilsenbeck SG;Mills GB;Brown PH
通讯作者：
Brown PH
影响因子：
4.7
作者：
Simon, Iris;Katsaros, Dionyssios;Diamandis, Eleftherios P.
通讯作者：
Diamandis, Eleftherios P.
影响因子：
11.5
作者：
Lo, Charlotte S.;Sanii, Sanaz;Nelson, Brad H.
通讯作者：
Nelson, Brad H.
影响因子：
11.5
作者：
Fucikova, Jitka;Rakova, Jana;Spisek, Radek
通讯作者：
Spisek, Radek