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. 2018 Mar 20;8(1):4899.
doi: 10.1038/s41598-018-23099-7.

Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer

Jhajaira M Araujo  1 , Andrea C Gomez  2 , Alfredo Aguilar  1 , Roberto Salgado  3 , Justin M Balko  4 , Leny Bravo  5 , Franco Doimi  1 , Denisse Bretel  1   6 , Zaida Morante  1   7 , Claudio Flores  1 , Henry L Gomez  8   9 , Joseph A Pinto  1
Affiliations

Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer

Jhajaira M Araujo et al. Sci Rep. .

Abstract

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited options of targeted therapy. Recent findings suggest that the clinical course of TNBC may be modified by the presence of tumor-infiltrating lymphocytes (TILs) and chemokine's expression, such as CCL5. Diverse studies have shown that CCL5 suppresses anti-tumor immunity and it has been related to poor outcome in different types of cancer while in other studies, this gene has been related with a better outcome. We sought to determine the association of CCL5 with the recruitment of TILs and other immune cells. With this aim we evaluated a retrospective cohort of 72 TNBC patients as well as publicly available datasets. TILs were correlated with residual tumor size after neoadjuvant chemotherapy (NAC) and CCL5 expression. In univariate analysis, TILs and CCL5 were both associated to the distant recurrence free survival; however, in a multivariate analysis, TILs was the only significant marker (HR = 0.336; 95%IC: 0.150-0.753; P = 0.008). CIBERSORT analysis suggested that a high CCL5 expression was associated with recruitment of CD8 T cells, CD4 activated T cells, NK activated cells and macrophages M1. The CD8A gene (encoding for CD8) was associated with an improved outcome in several public breast cancer datasets.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
A positive correlation between CCL5 and TILs count was observed in the Peruvian cohort (P = 0.003).
Figure 2
Figure 2
Expression of CCL5 was directly correlated with the expression of CD8A in all datasets.
Figure 3
Figure 3
CD8B expression was associated with CCL5 in 3 out 5 datasets of TNBC.
Figure 4
Figure 4
Meta-analysis of CCL5 in recurrence-free survival (RFS) in TNBC (using the median of expression as cutoff) in databases of KM plotter. A High expression of CCL5 was associated with good prognosis (P = 0.0012).
Figure 5
Figure 5
Relative fractions of 22 leukocyte subtypes (LM22 signature) evaluated by CIBERSORT in five TNBC datasets according to CCL5 expression (1st tertile vs 3rd tertile) (a). Differences between immune cell subtypes according to CCL5 expression. Analysis was limited to cases with CIBERSORT p-value < 0.05 (b).
Figure 6
Figure 6
Meta-analysis in KM-Plotter showed that an high expression of CD8A (a) and CD8B (b) are related with a better relapse free survival in TNBC. CD8A overexpression is related with better disease free survival in the TCGA (c) and better overall survival in the METABRIC (d) datasets (all breast cancer subtypes).
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