Identification and validation of a poor clinical outcome subtype of primary prostate cancer with Midkine abundance.
Identification and validation of a poor clinical outcome subtype of primary prostate cancer with Midkine abundance.
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具有 Midkine 丰度的原发性前列腺癌临床结果较差的亚型的鉴定和验证
作者：
最近的研究发现，中期因子（MDK）在免疫调节中起着关键作用。在这项研究中，我们的目的是发现前列腺癌（PCa）的临床意义和翻译相关性。我们回顾性分析了复旦大学附属华山医院（培训队列，n = 369）和中国前列腺癌联盟（验证队列，n = 390）的759例接受根治性前列腺癌切除术的患者。对来自癌症基因组图谱（TCGA）数据库（外部队列）的共325例PCa患者进行了分析，以进行探索。免疫景观和抗肿瘤免疫通过免疫组织化学和流式细胞术进行评估。应用患者源性外植体培养系统评价MDK的靶向潜力。我们发现肿瘤内MDK表达与PCa进展相关，这表明术后PCa患者的无生化复发（BCR）生存率不利。将MDK表达添加到术后风险评估工具CAPRA‐S中可以提高其预后价值。具有MDK丰度的肿瘤的特征在于肿瘤浸润性CD8+ T细胞具有较少的细胞毒性产生和增加的免疫检查点表达，这伴随着富集的免疫抑制性结构。此外，MDK抑制可以重新激活CD8+ T细胞抗肿瘤免疫。MDK mRNA表达与雄激素受体活性特征呈负相关，与放疗相关特征呈正相关。总之，MDK表达可作为PCa术后BCR的独立预测因子。MDK表达通过协调免疫逃避微环境损害CD8+ T细胞的抗肿瘤功能，这可以通过MDK抑制来逆转。此外，MDK富集的肿瘤对术后放疗具有潜在的敏感性，而对PCa的辅助激素治疗具有抵抗性。MDK可作为前列腺癌潜在的治疗靶点。
Recent studies identified Midkine (MDK) as playing a key role in immune regulation. In this study, we aimed to discover the clinical significance and translational relevance in prostate cancer (PCa). We retrospectively analyzed 759 PCa patients who underwent radical prostatectomy from Huashan Hospital, Fudan University (training cohort, n = 369) and Chinese Prostate Cancer Consortium (validation cohort, n = 390). A total of 325 PCa patients from The Cancer Genome Atlas (TCGA) database (external cohort) were analyzed for exploration. Immune landscape and antitumor immunity were assessed through immunohistochemistry and flow cytometry. Patient‐derived explant culture system was applied for evaluating the targeting potential of MDK. We found that intratumoral MDK expression correlated with PCa progression, which indicated an unfavorable biochemical recurrence (BCR)‐free survival for postoperative PCa patients. Addition of MDK expression to the postoperative risk assessment tool CAPRA‐S could improve its prognostic value. Tumors with MDK abundance characterized the tumor‐infiltrating CD8+ T cells with less cytotoxicity production and increased immune checkpoint expression, which were accompanied by enriched immunosuppressive contexture. Moreover, MDK inhibition could reactivate CD8+ T cell antitumor immunity. MDK mRNA expression negatively correlated with androgen receptor activity signature and positively associated with radiotherapy‐related signature. In conclusion, intratumoral MDK expression could serve as an independent prognosticator for BCR in postoperative PCa patients. MDK expression impaired the antitumor function of CD8+ T cells through orchestrating an immunoevasive microenvironment, which could be reversed by MDK inhibition. Moreover, tumors with MDK enrichment possessed potential sensitivity to postoperative radiotherapy while resistance to adjuvant hormonal therapy of PCa. MDK could be considered as a potential therapeutic target for PCa.
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影响因子：
8.8
作者：
Shimwell NJ;Bryan RT;Wei W;James ND;Cheng KK;Zeegers MP;Johnson PJ;Martin A;Ward DG
通讯作者：
Ward DG
影响因子：
8.2
作者：
Shafi AA;Schiewer MJ;de Leeuw R;Dylgjeri E;McCue PA;Shah N;Gomella LG;Lallas CD;Trabulsi EJ;Centenera MM;Hickey TE;Butler LM;Raj G;Tilley WD;Cukierman E;Knudsen KE
通讯作者：
Knudsen KE
影响因子：
28.2
作者：
Schiewer MJ;Goodwin JF;Han S;Brenner JC;Augello MA;Dean JL;Liu F;Planck JL;Ravindranathan P;Chinnaiyan AM;McCue P;Gomella LG;Raj GV;Dicker AP;Brody JR;Pascal JM;Centenera MM;Butler LM;Tilley WD;Feng FY;Knudsen KE
通讯作者：
Knudsen KE
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
11.5
作者：
Spratt, Daniel E.;Alshalalfa, Mohammed;Schaeffer, Edward M.
通讯作者：
Schaeffer, Edward M.