肿瘤细胞治疗研究
英文原题：Density and entropy of immune cells within the tumor microenvironment of primary tumors and matched brain metastases.
Density and entropy of immune cells within the tumor microenvironment of primary tumors and matched brain metastases.
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通过利用一个独特的配对原发肿瘤和 BM 组织样本队列，我们能够分别证明原发肿瘤中 TIL 密度更高，而 BM 中 TAM 密度更高。原发肿瘤中 CD3+、CD8+-TILs 和 CD163+-TAMs 的细胞密度较高与较短的 TTBM 相关，而原发肿瘤与 BM 之间 CD3+和 CD8+密度的较大差异与较长的 TTBM 相关。这些发现凸显了靶向 TAMs 作为减轻脑转移发展的治疗策略的潜力。
TIL（肿瘤浸润淋巴细胞）（TILs）和肿瘤相关巨噬细胞（TAMs）对实体瘤脑转移过程的影响日益受到报道。然而，关于原发肿瘤与脑转移（BM）之间个体内差异及其与临床结局参数相关性的数据仍然匮乏。
我们回顾性纳入了1990年1月至2022年10月期间接受原发肿瘤和BM切除的患者。通过对配对的肿瘤组织样本进行免疫组化染色，对TAMs（CD68+、CD163+）和TILs（CD3+、CD8+、CD45RO+、FOXP3+）进行密度定量。图像使用QuPath软件处理，生成的热图异质性通过Shannon熵进行测量。至BM时间（TTBM）定义为从原发肿瘤诊断到首次诊断BM的时间。
共纳入104例患者（46.2%为女性；BM诊断时中位年龄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。原发肿瘤样本中CD3+（p < 0.001）和CD8+-TILs（p < 0.001）密度更高，而匹配的BM中CD68+（p = 0.035）和CD163+-TAM密度更高（p < 0.001）。原发肿瘤中较高的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，原发肿瘤中观察到CD3+（p < 0.001）和FOXP3+（p = 0.011）TILs的熵更高。较长的TTBM与FOXP3+TILs较高的熵（p = 0.024）和CD163+TAMs较低的熵（p = 0.039）相关。未发现免疫细胞密度或熵与BM诊断后OS之间存在显著关联。
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.
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.
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.
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