Abstract
BackgroundTriple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. However, it is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer. In this study, we investigated how the cell composition of the immune cell infiltrated modifies the survival of patients with resected TNBC.MethodsRetrospectively, we collected data from 76 patients diagnosed with non-metastatic TNBC with available tissue blocks for tissue micro-array (TMA) construction. The TMA was constructed using two cores from each tumor block. The expression of CD4, CD8, FOXP3, CD20, CD68, CD163, PD-1, PD-L1, PTEN and phospho-STAT1 was determined by immunohistochemistry.ResultsWe observed that the inflammatory infiltrate in TNBC is enriched for M2 macrophages and T lymphocytes (CD4+, CD8+). PD-L1 expression in the stroma was associated with the percentage of TILs (p = 0.018) as, PD-L1 expression in the tumor was associated with the percentage of TILs (p = 0.049). We found a correlation between TILs and PD-L1 expression in stroma cells (p = 0.020) and in tumor cells (p = 0.027). In our cohort, we observed a trend for improved survival associated with higher CD8+ (p = 0.054) and CD4 + (p = 0.082) cell counts, but the results were not statistically significant. Conversely, the expression of PTEN in tumor cells and a low number of FOXP3+ cells in tumor stroma were both associated with improved OS. The CD8 to FOXP3 ratio and the CD4 to FOXP3 ratio were associated with better OS as well, however, only the CD8 to FOXP3 ratio had its prognostic impact confirmed in the METABRIC TNBC cohort. There was no association between PD-L1 expression and OS.ConclusionTNBC tumor microenvironment is enriched for lymphocytes and macrophages. FOXP3 expression and the CD8 to FOXP3 ratio in the tumor stroma as well as the loss of PTEN expression in tumor cells are prognostic factors in non-metastatic TNBC.
Highlights
Triple-negative breast cancer (TNBC) refers to breast carcinomas that lack the expression of hormone receptors, and that do not express the human epidermal growth factor receptor 2 (HER2) and do not have amplification of the corresponding gene (ERBB2)
TNBC tumor microenvironment is enriched for lymphocytes and macrophages
166 patients with HE slides available in the Pathology Department archive were selected for analysis of Tumor-infiltrating lymphocytes (TILs), and among them, 76 patients had paraffin blocks available, which were used to construct the tissue micro-array (TMA) for immunohistochemical analysis (Fig. 1)
Summary
Triple-negative breast cancer (TNBC) refers to breast carcinomas that lack the expression of hormone receptors (estrogen and progesterone receptors), and that do not express the human epidermal growth factor receptor 2 (HER2) and do not have amplification of the corresponding gene (ERBB2). TILs have been reported to be associated with better prognosis and higher response rates to neoadjuvant therapy in early-stage breast cancer as well as improved response to chemotherapy and trastuzumab [7], besides tumor infiltration by cells expressing CD3, CD8 and CD20 is a potential predictive biomarker of response to chemotherapy [8]. Triple-negative mammary carcinoma (TNBC) is an aggressive breast cancer subtype associated with dismal prognosis. The interaction between the immune system and the cancer cells plays a crucial role in tumor development and progression. It is still unclear how each diverse cell of the immune system contributes to the prognosis of patients with breast cancer.
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