Abstract
BackgroundThis study aimed to investigate the tumor-related infiltrating lymphocytes (TILs) affecting the response of trastuzumab and identify potential biomarkers based on immune-related genes to improve prognosis and clinical outcomes of targeted therapies in breast cancer.MethodsEstimation of stromal and immune cells in malignant tumors using expression data (ESTIMATE) was adopted to infer the fraction of stromal and immune cells through utilizing gene expression signatures in breast tumor samples. Cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) algorithm was applied to characterize cell composition of 22 lymphocytes from breast cancer tissues using their gene expression profiles. Immune-related genes were collected from the Immunology Database and Analysis (ImmPort). Univariate and multivariate Cox regression analyses were performed to identify the significant independent risk factors associated with poor overall survival (OS) and breast cancer-specific survival (BCSS) of breast cancer patients. Hub genes were identified based on the protein–protein interaction (PPI) network analysis.ResultsBased on the ESTIMATE algorithm, a significant reduction of stromal scores was observed in tumor tissues and pretreated tumor tissues compared with nontumor and posttreated tumor tissues, respectively, while immune scores failed to present notably statistical differences between both groups. However, from the results of the univariate Cox regression analysis, the immune score was identified to be remarkably associated with the poor OS for breast cancer patients. Subsequently, the infiltrating lymphocytes were evaluated in tumor tissues based on the CIBERSORT algorithm. Furthermore, significance analysis identified 1,244 differentially expressed genes (DEGs) from the GSE114082 dataset, and then 91 overlapping immune-related DEGs were screened between GSE114082 and ImmPort datasets. Subsequently, 10 top hub genes were identified and five (IGF1, ADIPOQ, PPARG, LEP, and NR3C1) significantly correlated with worse OS and BCSS on response to trastuzumab in breast cancer patients.ConclusionsThis study provided an insight into the immune score based on the tumor-related infiltrating lymphocytes in breast cancer tissues and demonstrates the benefits of immune infiltration on the treatment of trastuzumab. Meanwhile, the study established a novel five immune-related gene signature to predict the OS and BCSS of breast cancer treated by trastuzumab.
Highlights
The tumor microenvironment (TME) is composed of various cell types and extracellular components that are involved in each progression stage of oncogenesis [1]
To explore the proportion of infiltrating cells in tumor tissues, we utilized the ESTIMATE algorithm to assess two gene signatures: a stromal signature that represents the presence of stroma in tumor tissue and an immune signature that represents the attendance of immune cells in tumor tissue
The administration of targeted molecular therapy significantly decreased the stromal score in comparison with normal samples, but there was no statistical significance on the immune score between groups with targeted therapy or not (Figures 1C, D)
Summary
The tumor microenvironment (TME) is composed of various cell types (such as stromal cells, tumor cells, and immune cells) and extracellular components (such as cytokines, growth factors, hormones, etc.) that are involved in each progression stage of oncogenesis [1]. The TME does contribute to tumor initiation, progression, and metastasis and has a powerful effect on therapeutic responses. Tumorinfiltrating lymphocytes (TILs) comprised an extensive part of tumor-infiltrating immune cells and were considered to inhibit tumor growth resulting in the improved clinical outcomes of immuno- and chemotherapy in melanoma, colorectal cancer, and ovarian cancer [3–5]. Breast cancer was generally thought to have a weak immunogenicity, but recent studies have demonstrated high levels of TILs occurring in HER2+ and basal-like subtypes which are associated with good prognosis and with response to certain therapies [6, 7]. This study aimed to investigate the tumor-related infiltrating lymphocytes (TILs) affecting the response of trastuzumab and identify potential biomarkers based on immune-related genes to improve prognosis and clinical outcomes of targeted therapies in breast cancer
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