PO.TB10.19 · 肿瘤生物学
胸膜间皮瘤中CD163阳性肿瘤相关巨噬细胞空间分布的临床与预后意义
Clinical and prognostic significance of spatial distribution of CD163-positive tumor-associated macrophages in pleural mesothelioma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：尽管采用多模式治疗，胸膜间皮瘤（PM）仍是一种致命的恶性肿瘤。由石棉和肿瘤源性因子激活的巨噬细胞可能发展为具有促肿瘤特性的肿瘤相关巨噬细胞（TAMs）。然而，这些TAMs在PM中的空间分布和临床影响仍未明确界定。
方法：我们回顾性分析了1998至2010年间在京都大学医院和兵库县立尼崎综合医疗中心接受治疗的101例连续PM患者。进行CD163免疫组化以量化肿瘤内和肿瘤周区域的促肿瘤TAMs，同时用Ki-67染色评估肿瘤增殖。肿瘤内区域定义为肿瘤内部的区域，若不可行，则定义为含有≥70%肿瘤组织的视野。肿瘤周区域定义为含有>70%间质的邻近间质区域。TAM密度的最佳临界值采用结合治疗前C反应蛋白（CRP）的最小p值法确定。总生存（OS）采用Kaplan-Meier法估计，并采用Cox回归模型进行单变量和多变量分析，以检验影响生存的因素。
结果：肿瘤内和肿瘤周CD163阳性TAM密度分别为660.8±565.9和223.1±195.6 cells/mm²，两者中度相关（r=0.505，p<0.001）。肿瘤内和肿瘤周TAM密度均与CRP相关（r=0.283和0.255，p<0.05）以及与Ki-67相关（r=0.498和0.435，p<0.001）。肿瘤内TAMs在肉瘤样组织学（p<0.001）和晚期分期（p=0.043）中更为丰富，而肿瘤周TAMs与临床病理因素无显著关联。高CD163阳性TAM密度在两个区域均预示更差的OS：肿瘤内高与低组的5年OS率分别为13.3%和23.2%（p=0.044），肿瘤周高与低组的5年OS率分别为13.2%和24.1%（p=0.046）。在多变量分析中，肿瘤周CD163阳性TAM高状态（HR=1.700，95% CI 1.034-2.796，p=0.037）与分期和组织学一同仍是独立预后因素。
结论：在PM中，高密度的CD163阳性TAMs与全身炎症和肿瘤增殖相关。这些TAMs的空间分布可能提示一个与预后相关的肿瘤免疫微环境，尤其是肿瘤周TAMs显示出独立的预后意义。这些发现提示，TAM空间分析可能作为风险分层的一种实用生物标志物。
查看英文原文 English abstract
Objectives: Pleural mesothelioma (PM) remains a fatal malignancy despite multimodal therapy. Macrophages activated by asbestos and tumor-derived factors may develop into tumor-associated macrophages (TAMs) with tumor-promoting properties. However, the spatial distribution and clinical impact of these TAMs in PM remain poorly defined.
Methods: We retrospectively analyzed 101 consecutive patients with PM treated at Kyoto University Hospital and Hyogo Prefectural Amagasaki General Medical Center between 1998 and 2010. CD163 immunohistochemistry was performed to quantify pro-tumoral TAMs in intratumoral and peritumoral regions, while Ki-67 staining assessed tumor proliferation. The intratumoral region was defined as an area within the tumor or, if not feasible, as a field containing ≥70% tumor tissue. The peritumoral region was defined as an adjacent stromal area containing >70% stroma. Optimal cutoffs for TAM densities were determined using the minimum p-value method with pretreatment C-reactive protein (CRP). Overall survival (OS) was estimated using the Kaplan-Meier method, and the Cox regression model was employed for univariable and multivariable analyses to examine factors influencing survival.
Results: Intratumoral and peritumoral CD163-positive TAM densities were 660.8 ± 565.9 and 223.1 ± 195.6 cells/mm², respectively, and were moderately correlated (r = 0.505, p < 0.001). Both intratumoral and peritumoral TAM densities correlated with CRP (r = 0.283 and 0.255, p < 0.05) and Ki-67 (r = 0.498 and 0.435, p < 0.001). Intratumoral TAMs were more abundant in sarcomatoid histology (p < 0.001) and in advanced stage (p = 0.043), whereas peritumoral TAMs showed no significant associations with clinicopathologic factors. High CD163-positive TAM density predicted poorer OS in both regions: intratumoral high versus low groups showed 5-year OS rates of 13.3% and 23.2% (p = 0.044), and peritumoral high versus low groups showed 5-year OS rates of 13.2% and 24.1% (p = 0.046). In multivariable analysis, peritumoral CD163-positive TAM-high status (HR = 1.700, 95% CI 1.034-2.796, p = 0.037) remained an independent prognostic factor along with stage and histology.
Conclusions: In PM, high densities of CD163-positive TAMs were associated with systemic inflammation and tumor proliferation. The spatial distribution of these TAMs may indicate a prognostically relevant tumor immune microenvironment, and peritumoral TAMs in particular showed independent prognostic significance. These findings suggest that TAM spatial profiling may serve as a practical biomarker for risk stratification.
利益披露 Disclosure
R. Sumitomo, None..
T. Fukui, None..
M. Kobayashi, None..
H. Sakai, None..
T. Menju, None.