免疫因子與上皮性卵巢癌預後之關聯性

Abstract

上皮性卵巢癌是婦科癌症領域中相當重要的疾病。過去在卵巢癌的腫瘤減積手術技術、化學治療藥物及標靶藥物的使用方面已經累積了豐富的臨床經驗與研究成果，然而，一旦患者復發，則容易對化療藥物產生抗藥性，並造成後續藥物選擇的困難。近年來，許多研究聚焦於卵巢癌的腫瘤微環境及其中的免疫組成，企圖從腫瘤免疫學的觀點找尋新的治療策略，因此，本研究利用台灣上皮性卵巢癌患者的腫瘤組織進行四種常見的免疫檢查點：CTLA-4、PD-1、PD-L1及BTLA的分析，並進一步探討其表現量與各臨床因子及患者預後的關聯。 本研究於患者接受卵巢癌手術時蒐集部分癌組織並抽取RNA，利用四種免疫檢查點之引子進行即時定量聚合酶鏈反應以偵測其基因相對表現量，另蒐集正常卵巢組織作為對照組。研究發現卵巢癌組織比起正常卵巢組織表現較多的CTLA-4(P=0.016)與PD-1(P<0.001)。漿液性/子宮內膜樣腺癌表現較多的CTLA-4(P=0.044)、亮細胞癌/黏液性腺癌表現較多的PD-L1(P=0.003)、晚期患者則表現較多的CTLA-4(P=0.008)、PD-1(P=0.035)、BTLA(P=0.043)，另外術前CA-125較高的患者表現較多的CTLA-4(P=0.0097)及PD-1(P=0.015)。高CTLA-4表現量有較低的疾病復發風險(風險比：0.39，95%信賴區間：0.16-0.99，P=0.047)，除此之外，晚期癌症則為重要的疾病復發風險因子(風險比：12.68，95%信賴區間：4.14-38.85，P<0.001)及疾病死亡風險因子(風險比：13.63，95%信賴區間：1.48−125.26，P=0.021)。 總結而言，本研究發現不同組織型別、期別的卵巢癌組織在四種免疫檢查點的表現量不盡相同，而高CTLA-4表現量的患者有較低的疾病復發風險，然而本研究的侷限為收案人數不足，且晚期患者偏多及部分組織型別患者偏少，另外免疫檢查點可能同時表現在多種細胞表面，而本研究並未探究癌組織中的免疫細胞組成。因此，本研究之成果宜做為此議題之初探，未來宜增加收案人數並更深入的探討各免疫檢查點的分布及實質影響，以期能作為臨床預後的指標及藥物選擇的基準。

Epithelial ovarian cancer is a disease of considerable importance in the field of gynecological cancer. Rich clinical experiences and researches have been accumulated in the use of debulking surgery, adjuvant chemotherapy and target therapy. However, resistance to chemotherapy medication may occur once patients got disease recurrence, and it causes treatment difficulties. Many recent studies focus on the tumor microenvironment of ovarian cancer and its immune system components in an attempt to find new therapeutic strategies from the perspective of tumor immunology. Guided by these studies, this research analyzes the gene expression of the four common immune checkpoints: CTLA-4、PD-1、PD-L1 and BTLA, in Taiwanese epithelial ovarian cancerous tissue, and further explores the correlation between their expression levels with various clinical factors and patients’ prognoses. This study collects the cancerous tissue when patients underwent debulking surgery, extracts the RNAs from cancerous tissue, and performs real-time PCR after adding primers of the four immune checkpoints. The expression levels of these immune checkpoints are analyzed. Normal ovarian tissue is used as a control group. There are more CTLA-4(P=0.016) and PD-1(P<0.001) in the cancerous tissue than in the normal ovarian tissue. There are more CTLA-4(P=0.044) in serous/endometrioid adenocarcinoma, more PD-L1(P=0.003) in clear cell/mucinous adenocarcinoma, more CTLA-4(P=0.008)、PD-1(P=0.035)、BTLA(P=0.043) in advanced stage diseases. Patients with abnormally high CA-125 express more CTLA-4(P=0.0097) and PD-1(P=0.015). Patients with high CTLA-4 expression have a lower risk of recurrence (HR: 0.39, 95% CI: 0.16-0.99, P=0.047). Besides, patients with advanced stage diseases have a greater risk of recurrence (HR: 12.68, 95% CI: 4.14−38.85, P<0.001) and death (HR: 13.63, 95% CI: 1.48−125.26, P=0.021). In conclusion, this study finds that ovarian cancer tissue of different histological types and stages has different expression levels of the four immune checkpoints, and patients with high CTLA-4 expression have a lower risk of disease recurrence. However, there are some limitations of this study, including the limited case number, and the uneven proportion between different stages and histologies. In addition, immune checkpoints may be expressed on the surface of multiple cells at the same time, and this study does not explore the composition of immunocytes in cancerous tissue. Therefore, the results of this study should be used as a preliminary exploration of this topic. In the future, the number of cases should be increased and the distribution and substantial impact of each immune checkpoint should be discussed in more depth, in order to be used as an indicator of clinical prognosis and a benchmark for drug selection.