Experimental Therapeutics Unit, Medical Oncology Department, Hospital Clínico San Carlos (HCSC), Instituto de Investigación Sanitaria (IdISSC) and CIBERONC, Calle Del Prof Martín Lagos, s/n, 28040, Madrid, Spain.
Translational Research Unit, Translational Oncology Laboratory, Albacete University Hospital, Albacete, Spain.
Cell Oncol (Dordr). 2021 Jun;44(3):569-580. doi: 10.1007/s13402-020-00583-9. Epub 2021 Jan 19.
Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research.
The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation.
We identified 7 genes coding for integrin α and β subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters.
We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis.
整合素是一种跨膜受体，介导细胞-细胞外基质和细胞-细胞相互作用，与多种癌症相关特征有关。整合素在癌症中的一个较少被探索的功能是其在白细胞归巢和激活中的作用。了解它们与免疫细胞浸润和免疫检查点的关系是癌症研究的一个关注领域。
使用转录组学数据（Affymetrix 数据集，探索性队列）和 METABRIC 研究（验证队列）评估 33 种不同整合素的表达与乳腺癌患者预后的关系。使用 TIMER 在线工具评估鉴定的整合素基因与免疫细胞浸润的相关性，以及 TCGA 和 METABRIC 研究评估整合素基因表达与免疫激活的基因组特征之间的相关性。
我们确定了 7 个编码整合素 α 和 β 亚基的基因，即 ITGA4、ITGB2、ITGAX、ITGB7、ITGAM、ITGAL 和 ITGA8，它们预测基底样和 HER2+乳腺癌的预后良好。它们的表达与肿瘤内免疫细胞浸润的存在呈正相关（树突状细胞、CD4+T 细胞、中性粒细胞、CD8+T 细胞和 B 细胞），与 T 细胞激活和抗原呈递的标志物以及免疫监视的基因特征（细胞毒性 T 淋巴细胞激活和 IFNγ 特征）呈正相关。相比之下，我们发现预测不良预后的整合素基因（IBSP、ITGB3BP、ITGB6、ITGB1 和 ITGAV）与这些参数均无关联。
我们确定了一个由 7 个基因组成的整合素特征，具有识别免疫浸润和激活的基底样和 HER2+乳腺癌的潜力，这些乳腺癌具有良好的预后。
