Batman Samantha, Matsuo Koji, Mhawech-Fauceglia Paulette, Munro Elizabeth, Weisenberger Mercedes, Allen Allison, Joshi Sonali, Machida Hiroko, Matsuzaki Shinya, Bozanovic Tatjana, Pejovic Tanja
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA 90033, USA.
Cancers (Basel). 2021 Apr 20;13(8):1972. doi: 10.3390/cancers13081972.
Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC.
Immunohistochemical analysis of TMA with 181 EOC samples was used to determine expression levels for DNA repair proteins (PARP, PTEN, p53, H2Ax, FANCD2, and ATM) and immune-markers (CD4, CD8, CD68, PD-L2, PD-L1, and FOXP3). Biomarker expression was correlated to clinical data. Prognostic discriminatory ability was assessed per the combination of biomarkers.
Tumor immunity biomarkers correlated with HRD biomarkers. High PD-L2 was significantly associated with high expression of CD8 ( = 0.18), CD68 ( = 0.17), and FOXp3 ( = 0.16) (all, < 0.05). In a multivariate analysis, PD-L2 (hazard ratio (HR) 1.89), PARP (HR 1.75), and PTEN (HR 1.96) expressions were independently associated with decreased progression-free survival (PFS), whereas PD-L1 (HR 0.49) and CD4 (HR 0.67) were associated with improved PFS (all, < 0.05). In 15 biomarker combinations, six combinations exhibited a discriminatory ability of >20% for the 4.5-year PFS rate, with four based on PD-L2 (PARP, PTEN, CD4, and PD-L1, 20.5-30.0%).
Increased PD-L2 expression is a prognostic marker of decreased survival in EOC. Interaction between tumor DNA repair and microenvironment determines tumor progression and survival.
靶向DNA修复和免疫检查点通路一直是多项临床试验的重点。在本研究中，我们探讨了DNA修复蛋白、免疫反应标志物与上皮性卵巢癌（EOC）女性患者临床结局之间的关联。
采用免疫组织化学分析法对181例EOC样本的组织微阵列（TMA）进行检测，以确定DNA修复蛋白（PARP、PTEN、p53、H2Ax、FANCD2和ATM）和免疫标志物（CD4、CD8、CD68、PD-L2、PD-L1和FOXP3）的表达水平。将生物标志物表达与临床数据相关联。根据生物标志物的组合评估预后判别能力。
肿瘤免疫生物标志物与同源重组缺陷（HRD）生物标志物相关。高PD-L2表达与CD8（r = 0.18）、CD68（r = 0.17）和FOXp3（r = 0.16）的高表达显著相关（均P < 0.05）。在多变量分析中，PD-L2（风险比[HR] 1.89）、PARP（HR 1.75）和PTEN（HR 1.96）的表达与无进展生存期（PFS）缩短独立相关，而PD-L1（HR 0.49）和CD4（HR 0.67）与PFS改善相关（均P < 0.05）。在15种生物标志物组合中，6种组合对4.5年PFS率的判别能力>20%，其中4种基于PD-L2（PARP、PTEN、CD4和PD-L1，20.5 - 30.0%）。
PD-L2表达增加是EOC患者生存预后不良的标志物。肿瘤DNA修复与微环境之间的相互作用决定了肿瘤进展和生存。
