原发性肿瘤及其匹配的脑转移瘤的肿瘤微环境中免疫细胞的密度和熵
Density and entropy of immune cells within the tumor microenvironment of primary tumors and matched brain metastases.
作者信息
Kleinberger Markus, Çifçi Didem, Paiato Christina, Tomasich Erwin, Mair Maximilian J, Steindl Ariane, Spiró Zoltán, Carrero Zunamys I, Berchtold Luzia, Hainfellner Johannes, Müllauer Leonhard, Heller Gerwin, Preusser Matthias, Kather Jakob Niklas, Berghoff Anna Sophie
机构信息
Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria.
Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
出版信息
Acta Neuropathol Commun. 2025 Feb 19;13(1):34. doi: 10.1186/s40478-025-01939-8.
BACKGROUND
Tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) have increasingly been reported to impact the brain metastatic process of solid tumors. However, data on intra-individual differences between primary tumor and brain metastasis (BM), as well as their correlation with clinical outcome parameters, is scarce.
METHODS
We retrospectively identified patients who received resection of the primary tumor and BM between 01/1990 and 10/2022. Density quantification of TAMs (CD68, CD163) and TILs (CD3, CD8, CD45RO, FOXP3) was performed by immunohistochemical staining of matched tumor tissue samples. Images were processed with QuPath software and heterogeneity of generated heatmaps was measured by Shannon Entropy. Time-to-BM (TTBM) was defined as the time from diagnosis of the primary tumor until the first diagnosis of BM.
RESULTS
In total, 104 patients (46.2% female; median age 57.3 years at BM diagnosis) were included: 78/104 (75%) non-small cell lung cancer, 18/104 (17%) breast cancer, 8/104 (8%) renal cell carcinomas. Densities of CD3 (p < 0.001) and CD8-TILs (p < 0.001) were higher in primary tumor samples, while CD68 (p = 0.035) and CD163-TAM densities (p < 0.001) were higher in the matched BM. Higher CD3, CD8-TILs and CD163-TAMs densities in primary tumors were associated with shorter TTBM (p = 0.005, p = 0.015 and p = 0.006, respectively). Higher entropies of CD3 (p < 0.001) and FOXP3 (p = 0.011) TILs were observed in primary tumors compared to BM. Longer TTBM was associated with higher entropy of FOXP3 TILs (p = 0.024) and lower entropy in CD163 TAMs (p = 0.039). No significant associations of immune cell densities or entropies with OS after BM diagnosis were found.
DISCUSSION
By utilizing a unique cohort of matched primary tumor and BM tissue samples, we could demonstrate higher TIL densities in primary tumors and higher TAM densities in BM, respectively. Higher cell densities of CD3, CD8-TILs and CD163-TAMs in primary tumors were associated with shorter TTBM, while a larger difference between CD3 and CD8 densities between primary tumor and BM was associated with longer TTBM. These findings highlight the potential of targeting TAMs as a therapeutic strategy to mitigate the development of brain metastases.
背景
越来越多的研究报道肿瘤浸润淋巴细胞（TILs）和肿瘤相关巨噬细胞（TAMs）会影响实体瘤的脑转移过程。然而，关于原发性肿瘤与脑转移瘤（BM）之间个体内差异及其与临床结局参数相关性的数据却很少。
方法
我们回顾性地确定了1990年1月至2022年10月期间接受原发性肿瘤和BM切除术的患者。通过对匹配的肿瘤组织样本进行免疫组织化学染色，对TAMs（CD68、CD163）和TILs（CD3、CD8、CD45RO、FOXP3）进行密度定量分析。使用QuPath软件处理图像，并通过香农熵测量生成热图的异质性。脑转移时间（TTBM）定义为从原发性肿瘤诊断到首次诊断BM的时间。
结果
总共纳入了104例患者（女性占46.2%；BM诊断时的中位年龄为57.3岁）：78/104（75%）为非小细胞肺癌，18/104（17%）为乳腺癌，8/104（8%）为肾细胞癌。原发性肿瘤样本中CD3（p < 0.001）和CD8-TILs（p < 0.001）的密度较高，而匹配的BM中CD68（p = 0.035）和CD163-TAM密度（p < 0.001）较高。原发性肿瘤中较高的CD3、CD8-TILs和CD163-TAMs密度与较短的TTBM相关（分别为p = 0.005、p = 0.015和p = 0.006）。与BM相比，原发性肿瘤中CD3（p < 0.001）和FOXP3（p = 0.011）TILs的熵更高。较长的TTBM与FOXP3 TILs的较高熵（p = 0.024）和CD163 TAMs的较低熵（p = 0.039）相关。未发现免疫细胞密度或熵与BM诊断后的总生存期有显著关联。
讨论
通过利用一组独特的匹配原发性肿瘤和BM组织样本，我们分别证明了原发性肿瘤中较高的TIL密度和BM中较高的TAM密度。原发性肿瘤中较高的CD3、CD8-TILs和CD163-TAMs细胞密度与较短的TTBM相关，而原发性肿瘤与BM之间CD3和CD8密度的较大差异与较长的TTBM相关。这些发现突出了将TAMs作为减轻脑转移发展的治疗策略的潜力。
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