PO.TB10.06 · 肿瘤生物学
Vater壶腹癌的肿瘤微环境揭示CAF、TIL和TAM的独特空间微环境及其与临床病理特征的相关性
Tumor microenvironment of ampulla of Vater cancer reveals distinct spatial niche of CAF, TIL, and TAM and their correlation with clinicopathologic features
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摘要 Abstract
中文摘要
背景：
虽然癌相关成纤维细胞（CAFs）、肿瘤浸润淋巴细胞（TILs）和肿瘤相关巨噬细胞（TAMs）在Vater壶腹（AoV）癌肿瘤微环境（TME）中的各自作用已得到认识，但对它们协同相互作用的详细理解及其与临床病理特征和患者生存的相关性仍然缺乏。
方法：
选取了一个由87例接受切除的IB-III期AoV腺癌患者组成的回顾性队列（首尔圣玛丽医院，2007至2021年间）。构建TMA（2-mm组织芯），并对肿瘤细胞标志物（EGFR、HER2和c-MET）、TME标志物（CD3、CD8、FOXP3、CD68、CD163、alpha-SMA、FAP、PDPN和POSTN）进行免疫染色，并采用Masson三色（MT）染色检测纤维化。进行多重IF以进行高重数空间蛋白质组学分析（CellScape）。所有切片均数字化并分析，以量化免疫细胞密度（细胞/mm2）、间充质标志物H评分及空间关系（细胞间距离），从而界定TME微环境。使用R分析的主要终点为无病生存期（DFS）和总生存期（OS）。双侧p值<0.05被视为具有统计学意义。
结果：
TAM标志物与T细胞标志物呈显著正相关，但与CAF标志物呈负相关。FAP和POSTN彼此正相关，但与PDPN和IL6负相关。ACTA2和IL6与大多数其他标志物负相关，而彼此正相关。DFS的单变量Cox回归识别出高EGFR（HR=6.89，95% CI：2.94-16.20，p=0.026）、FAP（HR=2.21，95% CI：1.27-3.86，p=0.027）和高纤维化（MT）（HR=2.49，95% CI：1.42-4.37，p=0.008）为不良预后因素。CD3和POSTN对OS显示出接近预后意义的趋势（分别为p=0.07和p=0.06）。在多重IF中，空间分析显示TAMs（CD68和CD163）位于最靠近肿瘤细胞的位置，其次依序为CAF标志物（vimentin和SMA）、IV型胶原（Collagen IV），而TIL标志物距离最远。
结论：
我们的研究结果表明，AoV癌中的TME成分形成独特的空间微环境，其特征为TAMs邻近肿瘤细胞而TILs位于远端区域。这种特定的结构，尤其是当以高FAP和纤维化为主导时，与不良生存显著相关，突显了空间TME分析作为关键预后工具的重要性。
查看英文原文 English abstract
Background:
While the individual roles of cancer-associated fibroblasts (CAFs), tumor-infiltrating lymphocytes (TILs), and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) of ampulla of Vater (AoV) carcinomas are recognized, a detailed understanding of their collective interplay and its correlation with clinicopathologic features and patient survival is still lacking.
Methods:
A retrospective cohort of 87 patients with resected stage IB-III AoV adenocarcinoma (Seoul St. Mary's Hospital between 2007 and 2021) was selected. TMAs (2-mm cores) were constructed and immunostained for tumor cell markers (EGFR, HER2, and c-MET), TME markers (CD3, CD8, FOXP3, CD68, CD163, alpha-SMA, FAP, PDPN, and POSTN), and Masson's Trichrome (MT) staining for fibrosis. Multiplex IF was performed for high-plex spatial proteomic analysis (CellScape). All slides were digitized and analyzed to quantify the immune cell densities (cells/mm2), mesenchymal marker H-scores, and spatial relationships (cell-cell distance) to define the TME niches. The primary endpoints analyzed using R were disease-free survival (DFS) and overall survival (OS). A two-sided p-value of <0.05 was considered to be statistically significant.
Results:
TAM markers showed a significant positive correlation with T-cell markers but a negative association with CAF markers. FAP and POSTN were positively correlated with each other but negatively correlated with PDPN and IL6. ACTA2 and IL6 were negatively correlated with most other markers, while being positively correlated with each other. Univariate Cox regression for DFS identified high EGFR (HR=6.89, 95% CI: 2.94-16.20, p=0.026), FAP (HR=2.21, 95% CI: 1.27-3.86, p=0.027), and high fibrosis (MT) (HR=2.49, 95% CI: 1.42-4.37, p=0.008) as unfavorable prognostic factors. CD3 and POSTN showed a trend towards prognostic significance for OS (p=0.07 and p=0.06, respectively). In multiplex IF, spatial analysis revealed that TAMs (CD68 and CD163) were located closest to the tumor cells, followed sequentially by CAF markers (vimentin and SMA), Collagen IV, and TIL markers, which were the most distant.
Conclusions:
Our findings demonstrate that TME components in AoV carcinoma form distinct spatial niches, characterized by TAMs proximal to tumor cells and TILs in the distal region. This specific architecture, especially when dominated by high FAP and fibrosis, is significantly associated with poor survival, highlighting the importance of spatial TME analysis as a critical prognostic tool.
利益披露 Disclosure
Y. Jeong, None..
S. Park, None..
S. Lee*, None..
Y. Kim*, None.