Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Pathology, Vestfold Hospital, Tønsberg, Norway.
J Pathol Clin Res. 2021 Sep;7(5):517-527. doi: 10.1002/cjp2.226. Epub 2021 Jun 2.
The tumor microenvironment plays a critical role in breast cancer progression. Here, we investigated tumor-infiltrating lymphocytes (TILs) and associations with macrophage numbers, tumor stromal elastosis, vascular invasion, and tumor detection mode. We performed a population-based retrospective study using data from The Norwegian Breast Cancer Screening Program in Vestfold County (2004-2009), including 200 screen-detected and 82 interval cancers. The number of TILs (CD45+, CD3+, CD4+, CD8+, and FOXP3+) and tumor-associated macrophages (CD163+) was counted using immunohistochemistry on tissue microarray slides. Lymphatic and blood vessel invasion (LVI and BVI) were recorded using D2-40 and CD31 staining, and the amount of elastosis (high/low) was determined on regular HE-stained slides. High numbers of all TIL subsets were associated with LVI (p ≤ 0.04 for all), and high counts of several TIL subgroups (CD8+, CD45+, and FOXP3+) were associated with BVI (p ≤ 0.04 for all). Increased levels of all TIL subsets, except CD4+, were associated with estrogen receptor-negative tumors (p < 0.001) and high tumor cell proliferation by Ki67 (p < 0.001). Furthermore, high levels of all TIL subsets were associated with high macrophage counts (p < 0.001) and low-grade stromal elastosis (p ≤ 0.02). High counts of CD3+, CD8+, and FOXP3+ TILs were associated with interval detected tumors (p ≤ 0.04 for all). Finally, in the luminal A subgroup, high levels of CD3+ and FOXP3+ TILs were associated with shorter recurrence-free survival, and high counts of FOXP3+ were linked to reduced breast cancer-specific survival. In conclusion, higher levels of different TIL subsets were associated with stromal features such as high macrophage counts (CD163+), presence of vascular invasion, absence of stromal elastosis, as well as increased tumor cell proliferation and interval detection mode. Our findings support a link between immune cells and vascular invasion in more aggressive breast cancer. Notably, presence of TIL subsets showed prognostic value within the luminal A category.
肿瘤微环境在乳腺癌的进展中起着关键作用。在这里，我们研究了肿瘤浸润淋巴细胞（TILs）与巨噬细胞数量、肿瘤间质弹性蛋白、血管浸润和肿瘤检测模式之间的关系。我们进行了一项基于人群的回顾性研究，使用了来自 Vestfold 郡挪威乳腺癌筛查项目（2004-2009 年）的数据，包括 200 例筛查发现的肿瘤和 82 例间隔期肿瘤。使用组织微阵列载玻片上的免疫组织化学方法计数 TILs（CD45+、CD3+、CD4+、CD8+和 FOXP3+）和肿瘤相关巨噬细胞（CD163+）的数量。使用 D2-40 和 CD31 染色记录淋巴管和血管浸润（LVI 和 BVI），并在常规 HE 染色切片上确定弹性蛋白的量（高/低）。所有 TIL 亚群数量较高均与 LVI 相关（所有 p 值均 ≤ 0.04），而一些 TIL 亚组（CD8+、CD45+和 FOXP3+）数量较高与 BVI 相关（所有 p 值均 ≤ 0.04）。除 CD4+外，所有 TIL 亚群水平升高均与雌激素受体阴性肿瘤相关（p < 0.001），Ki67 高肿瘤细胞增殖也相关（p < 0.001）。此外，所有 TIL 亚群水平升高均与巨噬细胞计数较高（p < 0.001）和低级别间质弹性蛋白相关（p ≤ 0.02）。CD3+、CD8+和 FOXP3+TIL 计数较高与间隔期发现的肿瘤相关（所有 p 值均 ≤ 0.04）。最后，在 luminal A 亚组中，CD3+和 FOXP3+TIL 水平升高与无复发生存时间较短相关，FOXP3+计数升高与乳腺癌特异性生存时间缩短相关。总之，不同 TIL 亚群水平升高与高巨噬细胞计数（CD163+）、存在血管浸润、缺乏间质弹性蛋白、增加肿瘤细胞增殖和间隔期检测模式等基质特征相关。我们的发现支持免疫细胞与侵袭性乳腺癌中的血管浸润之间存在关联。值得注意的是，TIL 亚群的存在在 luminal A 类别中具有预后价值。
