Heterogeneity of the Tumor Microenvironment Across Molecular Subtypes of Breast Cancer.

IF 1.3 4区 医学 Q3 ANATOMY & MORPHOLOGY Applied Immunohistochemistry & Molecular Morphology Pub Date : 2023-09-01 Epub Date: 2023-06-26 DOI:10.1097/PAI.0000000000001139
Dharambir Kashyap, Amanjit Bal, Santosh Irinike, Siddhant Khare, Shalmoli Bhattacharya, Ashim Das, Gurpreet Singh
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Abstract

Breast cancer is a heterogenous disease at the molecular level thus, it can be hypothesized that different molecular subtypes differ in their tumor microenvironment (TME) also. Understanding the TME heterogeneity may provide new prognostic biomarkers and new targets for cancer therapy. For deciphering heterogeneity in the TME, immunohistochemistry for immune markers (CD3, CD4, CD8, CD68, CD163, and programmed death-ligand 1), Cancer-associated fibroblast markers [anti-fibroblast activating protein α (FAP-α), platelet-derived growth factor receptor α (PDGFR-α), S100A4, Neuron-glial antigen 2, and Caveolin-1], and angiogenesis (CD31) was performed on tissue microarrays of different molecular subtypes of breast cancer. High CD3 + T cells were noted in the Luminal B subtype ( P =0.002) of which the majority were CD8 + cytotoxic T cells. Programmed death-ligand 1 expression in immune cells was highest in the human epidermal growth factor receptor 2 (Her-2)-positive and Luminal B subtypes compared with the triple-negative breast cancer (TNBC) subtype ( P =0.003). Her-2 subtype is rich in M2 tumor-associated macrophages ( P =0.000) compared with TNBC and Luminal B subtypes. M2 immune microenvironment correlated with high tumor grade and high Ki-67. Her-2 and TNBC subtypes are rich in extracellular matrix remodeling (FAP-α, P =0.003), angiogenesis-promoting (PDGFR-α; P =0.000) and invasion markers (Neuron-glial antigen 2, P =0.000; S100A4, P =0.07) compared with Luminal subtypes. Mean Microvessel density showed an increasing trend: Luminal A>Luminal B>Her-2 positive>TNBC; however, this difference was not statistically significant. The cancer-associated fibroblasts (FAP-α, PDGFR-α, and Neuron-glial antigen 2) showed a positive correlation with lymph node metastasis in specific subtypes. Immune cells, tumor-associated macrophage, and cancer-associated fibroblast-related s tromal markers showed higher expression in Luminal B, Her-2 positive, and TNBC respectively. This differential expression of different components of TME indicates heterogeneity of the TME across molecular subtypes of breast cancer.

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癌症分子亚型肿瘤微环境的异质性。
癌症是一种分子水平上的异质性疾病,因此,可以假设不同的分子亚型在其肿瘤微环境(TME)中也有所不同。了解TME的异质性可能为癌症治疗提供新的预后生物标志物和新的靶点。为了破解TME中的异质性,免疫标记物(CD3、CD4、CD8、CD68、CD163和程序性死亡1)、癌症相关成纤维细胞标记物[抗成纤维细胞活化蛋白α(FAP-α)、血小板衍生生长因子受体α(PDGFR-α)、S100A4、神经元胶质抗原2和Caveolin-1]的免疫组织化学,在癌症不同分子亚型的组织微阵列上进行血管生成(CD31)。在Luminal B亚型中观察到高CD3+T细胞(P=0.002),其中大多数是CD8+细胞毒性T细胞。与癌症(TNBC)三阴性亚型相比,人表皮生长因子受体2(Her-2)阳性和Luminal B亚型的免疫细胞中程序性死亡配体1表达最高(P=0.003)。与TNBC和Luminal B亚型相比Her-2亚型富含M2肿瘤相关巨噬细胞(P=0.000)。M2免疫微环境与高肿瘤分级和高Ki-67相关。与Luminal亚型相比,Her-2和TNBC亚型富含细胞外基质重塑(FAP-α,P=0.003)、血管生成促进(PDGFR-α;P=0.000)和侵袭标记物(神经元-胶质抗原2,P=0.000;S100A4,P=0.007)。平均微血管密度呈增加趋势:管腔A>管腔B>Her-2阳性>TNBC;然而,这种差异在统计学上并不显著。癌症相关成纤维细胞(FAP-α、PDGFR-α和神经元胶质抗原2)在特定亚型中与淋巴结转移呈正相关。免疫细胞、肿瘤相关巨噬细胞和癌症相关成纤维细胞相关基质标记物分别在Luminal B、Her-2阳性和TNBC中表达较高。TME不同成分的差异表达表明TME在癌症分子亚型中的异质性。
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来源期刊
Applied Immunohistochemistry & Molecular Morphology
Applied Immunohistochemistry & Molecular Morphology ANATOMY & MORPHOLOGY-MEDICAL LABORATORY TECHNOLOGY
CiteScore
3.20
自引率
0.00%
发文量
153
期刊介绍: ​Applied Immunohistochemistry & Molecular Morphology covers newly developed identification and detection technologies, and their applications in research and diagnosis for the applied immunohistochemist & molecular Morphologist. Official Journal of the International Society for Immunohistochemisty and Molecular Morphology​.
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