Identification of immune-related biomarkers for predicting neoadjuvant chemotherapy sensitivity in HER2 negative breast cancer via bioinformatics analysis

Abstract

Background: Neoadjuvant chemotherapy (NAC) is an important treatment for breast cancer (BC) patients.However, due to the lack of specific therapeutic targets, only 1/3 of human epidermal growth factor receptor 2 (HER2)-negative patients reach pathological complete response (pCR). Therefore, there is an urgent need to identify novel biomarkers to distinguish and predict NAC sensitive in BC patients.Methods: The GSE163882 dataset, containing 159 BC patients treated with NAC, was downloaded from the Gene Expression Omnibus (GEO) database. Patients with pathological complete response (pCR) and those with residual disease (RD) were compared to obtain the differentially expressed genes (DEGs).Functional enrichment analyses were conducted on these DEGs. Then, we intersect the DEGs and immunerelated genes to obtain the hub immune biomarkers, and then use the linear fitting model ("glm" package) to construct a prediction model composed of 9 immune biomarkers. Finally, the single sample gene set enrichment analysis (ssGSEA) algorithm was used to analyze immune cell invasion in BC patients, and the correlation between immune cell content and immune gene expression levels was analyzed.Results: Nine immune-related biomarkers were obtained in the intersection of DEGs and immune-related genes. Compared with RD patients, CXCL9, CXCL10, CXCL11, CXCL13, GZMB, IDO1, and LYZ were highly expressed in pCR patients, while CXCL14 and ESR1 were lowly expressed in pCR patients. After linear fitting of the multi-gene expression model, the area under the curve (AUC) value of the ROC curve diagnosis of pCR patients was 0.844. Immunoinfiltration analysis showed that compared with RD patients, 15 of the 28 immune cell types examined showed high-infiltration in pCR patients, including activated CD8 T cells, effector memory CD8 T cells, and activated CD4 T cells.Conclusions: This investigation ultimately identified 9 immune-related biomarkers as potential tools for assessing the sensitivity of NAC in HER2-negative BC patients. These biomarkers have great potential for predicting pCR BC patients.

Association of immune‐related expression profile with sensitivity to chemotherapy in esophageal squamous cell carcinoma

“…Several previous studies have also demonstrated the association of chemotherapy efficacy with immune system‐related expression profiles or immune cell infiltration in preNAC biopsy samples. Fang et al identified immune‐related biomarkers predictive of NAC efficacy by using gene expression profiles of breast cancer patients 26 . The genes identified in their report, such as CXCL9 , CXCL10 , CXCL11 , CXCL13 , GZMB , IDO1 , and LYZ , were very similar to those in our study, suggesting a shared biological mechanism for chemosensitivity between esophageal and breast cancers.…”

“…Interestingly, we also found that some CD68‐negative stromal cells (non‐macrophage stromal cells) also expressed CXCL9 (Figure 5D–F ). Considering that previous reports have suggested T cells as the source of CXCL9, 25 , 26 it is possible that T cells in the biopsy samples also expressed CXCL9. Further studies are required to address this possibility.…”

“…Fang et al identified immune-related biomarkers predictive of NAC efficacy by using gene expression profiles of breast cancer patients. 26 The genes identified in their report, such as 32 Thus, an association between the immune profile of pre-chemotherapy tissue and chemosensitivity is becoming more evident based on data from several research groups. 33,34 However, the mechanism underlying interactions between the immune microenvironment and cancer cells is very complicated, and therefore more data will be required to establish a predictive method and suitable targeting therapy in a clinical setting.…”

“…(Figure 5D-F). Considering that previous reports have suggested T cells as the source of CXCL9, 25,26 it is possible that T cells in the biopsy samples also expressed CXCL9. Further studies are required to address this possibility.…”

Enhanced antitumour immunity following neoadjuvant chemoradiotherapy mediates a favourable prognosis in women with resected pancreatic cancer

“…CXCL10 and CXCL11 are proinflammatory cytokines that promote antitumour immunity 45 and were found to be associated with the prevention of M2 macrophage polarisation in PDAC 46 47 and glioblastoma. 48 In addition, elevated levels of these cytokines were associated with an improved (immunological) response to nCRT in rectal cancer 49 and breast cancer 50 and positively correlated to prolonged survival in PDAC patients treated with chemotherapy. 51 In contrast, elevated serum levels of the cytokine CCL2 were found to be associated with poor PDAC survival, 52 and both CCL2 and IL34 promote M2 macrophage polarisation.…”