Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Pathology, Oslo University Hospital-Rikshospitalet, Oslo, Norway.
Cell Oncol (Dordr). 2024 Aug;47(4):1267-1276. doi: 10.1007/s13402-024-00926-w. Epub 2024 Feb 26.
Tumor-associated macrophages (TAMs) are associated with unfavorable patient prognosis in many cancer types. However, TAMs are a heterogeneous cell population and subsets have been shown to activate tumor-infiltrating T cells and confer a good patient prognosis. Data on the prognostic value of TAMs in colorectal cancer are conflicting. We investigated the prognostic effect of TAMs in relation to tumor-infiltrating T cells in colorectal cancers.
The TAM markers CD68 and CD163 were analyzed by multiplex fluorescence immunohistochemistry and digital image analysis on tissue microarrays of 1720 primary colorectal cancers. TAM density in the tumor stroma was scored in relation to T cell density (stromal CD3 and epithelial CD8 cells) and analyzed in Cox proportional hazards models of 5-year relapse-free survival. Multivariable survival models included clinicopathological factors, MSI status and BRAF mutation status.
High TAM density was associated with a favorable 5-year relapse-free survival in a multivariable model of patients with stage I-III tumors (p = 0.004, hazard ratio 0.94, 95% confidence interval 0.90-0.98). However, the prognostic effect was dependent on tumoral T-cell density. High TAM density was associated with a good prognosis in patients who also had high T-cell levels in their tumors, while high TAM density was associated with poorer prognosis in patients with low T-cell levels (p = 0.0006). This prognostic heterogeneity was found for microsatellite stable tumors separately.
This study supported a phenotypic heterogeneity of TAMs in colorectal cancer, and showed that combined tumor immunophenotyping of multiple immune cell types improved the prediction of patient prognosis.
在许多癌症类型中，肿瘤相关巨噬细胞（TAMs）与患者预后不良相关。然而，TAMs 是一种异质性细胞群体，亚群已被证明能激活肿瘤浸润 T 细胞，并赋予患者良好的预后。关于 TAMs 在结直肠癌中的预后价值的数据存在争议。我们研究了 TAMs 与结直肠癌中肿瘤浸润 T 细胞的关系对预后的影响。
采用多重荧光免疫组织化学和组织微阵列的数字图像分析，分析了 1720 例原发性结直肠癌组织中 TAM 标志物 CD68 和 CD163。根据 T 细胞密度（基质 CD3 和上皮 CD8 细胞）对肿瘤基质中 TAM 密度进行评分，并在 5 年无复发生存的 Cox 比例风险模型中进行分析。多变量生存模型包括临床病理因素、MSI 状态和 BRAF 突变状态。
在 I-III 期肿瘤患者的多变量模型中，高 TAM 密度与 5 年无复发生存率相关（p=0.004，风险比 0.94，95%置信区间 0.90-0.98）。然而，这种预后效应取决于肿瘤内 T 细胞密度。在肿瘤内 T 细胞水平较高的患者中，高 TAM 密度与良好的预后相关，而在肿瘤内 T 细胞水平较低的患者中，高 TAM 密度与较差的预后相关（p=0.0006）。这种预后异质性在微卫星稳定肿瘤中分别存在。
本研究支持结直肠癌中 TAMs 的表型异质性，并表明对多种免疫细胞类型的联合肿瘤免疫表型分析可提高对患者预后的预测。
