Benefits of Targeted Molecular Therapy to Immune Infiltration and Immune-Related Genes Predicting Signature in Breast Cancer.

BACKGROUND

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.

METHODS

Estimation 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.

RESULTS

Based 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.

CONCLUSIONS

This 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.