A CTL/M2 Macrophage-Related Four-Gene Signature Predicting Metastasis-Free Survival in Triple-Negative Breast Cancer Treated with Adjuvant Radiotherapy

Abstract Purpose This study aimed to develop and validate a prognostic model for metastasis-free survival (MFS) based on genes that may functionally interact with cytotoxic T lymphocytes (CTLs) and M2 macrophages in patients with triple-negative breast cancer (TNBC) who underwent adjuvant radiotherapy.Methods The transcriptional profiles and phenotypical files of TNBC and other subtypes of breast cancer were downloaded from the Gene Expression Omnibus (GEO). The abundance of infiltrated immune cells was evaluated through CIBERSORTx or MCP-counter. A weighted linear model, the score for MFS (SMFS), was developed by using least absolute shrinkage and selection operator (LASSO) in GSE58812 and validated in GSE2034 and GSE12276. The biological implication of SMFS was explored by evaluating its associations with TNBC molecular subtypes and other radiosensitivity- or immune-related signatures. Results A model consisting of the gene expression ratios of PCDH12/ELP3, PCDH12/MSRA and FAM160B2/MSRA with nonzero coefficients finally selected by LASSO was developed in GSE58812. In GSE2034 (treatment with adjuvant radiotherapy), SMFS was significantly associated with MFS in TNBC patients (HR=8.767, 95% CI: 1.856-41.408, P=0.006) and, to a lesser extent, in non-TNBC patients (HR=2.888, 95% CI: 1.076-7.750, P=0.035). However, the interaction of subtype (TNBC vs non-TNBC) and SMFS tended to be significant (Pinteraction=0.081). In contrast, SMFS was not significantly associated with MFS in either TNBC patients (P=0.499) or non-TNBC patients (P=0.536) in GSE12276 (treatment without radiotherapy). Among the four TNBC molecular subtypes, the c1 and c4 subtypes exhibited higher CTL infiltration and lower SMFS values than the c2 and c3 subtypes. In addition, SMFS was positively correlated with the abundance of endothelial cells (r=0.413, P<0.001).Conclusions The proposed model has the potential to predict MFS in TNBC patients after adjuvant radiotherapy. SMFS may represent a measurement of tumor immune suppression.