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. 2020 Sep;27(5):880-892.
doi: 10.1007/s12282-020-01084-1. Epub 2020 Mar 28.

Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast

Tsengelmaa Jamiyan  1   2 , Hajime Kuroda  3 , Rin Yamaguchi  4 , Yoshimasa Nakazato  1 , Shuhei Noda  1 , Masato Onozaki  1 , Akihito Abe  5   6 , Mitsuhiro Hayashi  5
Affiliations

Prognostic impact of a tumor-infiltrating lymphocyte subtype in triple negative cancer of the breast

Tsengelmaa Jamiyan et al. Breast Cancer. 2020 Sep.

Abstract

Background: Tumor-infiltrating lymphocytes (TILs) have recently been reported as an important factor in the tumor microenvironment and influence the growth and progression of cancer. However, the relationship between immune cell subpopulations, such as CD4+, CD8+, and FOXP3+, in breast cancer, especially in triple negative carcinoma (TNC), remains unclear.

Methods: The subjects were 107 patients with TNC that were surgically resected at Dokkyo Medical University Hospital between 2006 and 2018. The expression of CD4+, CD8+, and FOXP3+ was evaluated in TILs and expressed as the numbers of positive cells.

Results: Univariate analysis revealed that the TILs were not prognostically significant. In multivariate analyses, increased infiltration of intratumoral (i) CD4+ TILs was found to have a good prognosis in relapse-free survival (RFS). In contrast, a high stromal CD8+ TILs level was found to be a favorable prognostic factor in RFS (p = 0.038) and overall survival (OS) (p = 0.046). A low sFOXP3 + TILs level was significantly associated with favorable RFS (p < 0.001) and OS (p = 0.029).

Conclusions: The present study demonstrated no difference in TILs and survival in TNC. However, there was a significant correlation in prognosis with levels of iCD4+, sCD8+, and sFOXP3 + TILs in TNC. The difference in TNC clinical outcome may be due to the subtype of the infiltrating TILs.

Keywords: Breast; CD4; CD8; FOXP3; Triple negative cancer.

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Conflict of interest statement

The authors declare no potential competing interests.

Figures

Fig. 1
Fig. 1
Triple-negative carcinoma of the breast. a Representative H&E staining images of iTILs and sTILs. b–d Representative images of immunohistochemical staining of low and high CD4+, CD8+ and FOXP3 + TILs infiltration densities in intratumoral and stromal areas. b CD4 + TILs, c CD8 + TILs, and d FOXP3 + TILs. Original magnification: ×400
Fig. 2
Fig. 2
a Recurrence-free survival (RFS) and overall survival (OS) in patients with iCD4 + TILs, iCD8 + TILs, and iFOXP3 + TILs. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low iCD4 + TILs, those of RFS (c) and OS (d) in patients with high or low iCD8 + TILs, and those of RFS (e) and OS (f) in patients with high or low iFOXP3 + TILs. b Prognostic significance of lymphocytic variables in breast cancer. Kaplan–Meier curves for overall survival (OS) and relapse-free survival (RFS) were stratified by the median values as the cut-off for prognostic evaluation and divided into low or high lymphocytic variable subsets. The blue solid line indicates patients with low values and the red solid line high values. sCD4 + TILs did not demonstrate prognostic significance for RFS (a) and OS (b), but high sCD8 + TILs was associated with both prolonged RFS (c) and OS (d). In contrast, high sFOXP3 + TILs was associated with both reduced RFS (e) and OS (f). c Kaplan–Meier survival curves illustrating the relapse-free survival (RFS) and overall survival (OS) according to the ratio of iCD4/CD8 (a, b), iCD8/FOXP3 (c, d) and iFOXP3/CD4 (e, f). d Recurrence-free survival (RFS) and overall survival (OS) in patients with different sCD4/CD8, sCD8/FOXP3, and sFOXP3/CD4 ratios. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low sCD4/CD8 ratios, those of RFS (c) and OS (d) in patients with high or low sCD8/FOXP3 ratios, and those of RFS (e) and OS (f) in patients with high or low sFOXP3/CD4 ratios
Fig. 2
Fig. 2
a Recurrence-free survival (RFS) and overall survival (OS) in patients with iCD4 + TILs, iCD8 + TILs, and iFOXP3 + TILs. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low iCD4 + TILs, those of RFS (c) and OS (d) in patients with high or low iCD8 + TILs, and those of RFS (e) and OS (f) in patients with high or low iFOXP3 + TILs. b Prognostic significance of lymphocytic variables in breast cancer. Kaplan–Meier curves for overall survival (OS) and relapse-free survival (RFS) were stratified by the median values as the cut-off for prognostic evaluation and divided into low or high lymphocytic variable subsets. The blue solid line indicates patients with low values and the red solid line high values. sCD4 + TILs did not demonstrate prognostic significance for RFS (a) and OS (b), but high sCD8 + TILs was associated with both prolonged RFS (c) and OS (d). In contrast, high sFOXP3 + TILs was associated with both reduced RFS (e) and OS (f). c Kaplan–Meier survival curves illustrating the relapse-free survival (RFS) and overall survival (OS) according to the ratio of iCD4/CD8 (a, b), iCD8/FOXP3 (c, d) and iFOXP3/CD4 (e, f). d Recurrence-free survival (RFS) and overall survival (OS) in patients with different sCD4/CD8, sCD8/FOXP3, and sFOXP3/CD4 ratios. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low sCD4/CD8 ratios, those of RFS (c) and OS (d) in patients with high or low sCD8/FOXP3 ratios, and those of RFS (e) and OS (f) in patients with high or low sFOXP3/CD4 ratios
Fig. 2
Fig. 2
a Recurrence-free survival (RFS) and overall survival (OS) in patients with iCD4 + TILs, iCD8 + TILs, and iFOXP3 + TILs. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low iCD4 + TILs, those of RFS (c) and OS (d) in patients with high or low iCD8 + TILs, and those of RFS (e) and OS (f) in patients with high or low iFOXP3 + TILs. b Prognostic significance of lymphocytic variables in breast cancer. Kaplan–Meier curves for overall survival (OS) and relapse-free survival (RFS) were stratified by the median values as the cut-off for prognostic evaluation and divided into low or high lymphocytic variable subsets. The blue solid line indicates patients with low values and the red solid line high values. sCD4 + TILs did not demonstrate prognostic significance for RFS (a) and OS (b), but high sCD8 + TILs was associated with both prolonged RFS (c) and OS (d). In contrast, high sFOXP3 + TILs was associated with both reduced RFS (e) and OS (f). c Kaplan–Meier survival curves illustrating the relapse-free survival (RFS) and overall survival (OS) according to the ratio of iCD4/CD8 (a, b), iCD8/FOXP3 (c, d) and iFOXP3/CD4 (e, f). d Recurrence-free survival (RFS) and overall survival (OS) in patients with different sCD4/CD8, sCD8/FOXP3, and sFOXP3/CD4 ratios. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low sCD4/CD8 ratios, those of RFS (c) and OS (d) in patients with high or low sCD8/FOXP3 ratios, and those of RFS (e) and OS (f) in patients with high or low sFOXP3/CD4 ratios
Fig. 2
Fig. 2
a Recurrence-free survival (RFS) and overall survival (OS) in patients with iCD4 + TILs, iCD8 + TILs, and iFOXP3 + TILs. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low iCD4 + TILs, those of RFS (c) and OS (d) in patients with high or low iCD8 + TILs, and those of RFS (e) and OS (f) in patients with high or low iFOXP3 + TILs. b Prognostic significance of lymphocytic variables in breast cancer. Kaplan–Meier curves for overall survival (OS) and relapse-free survival (RFS) were stratified by the median values as the cut-off for prognostic evaluation and divided into low or high lymphocytic variable subsets. The blue solid line indicates patients with low values and the red solid line high values. sCD4 + TILs did not demonstrate prognostic significance for RFS (a) and OS (b), but high sCD8 + TILs was associated with both prolonged RFS (c) and OS (d). In contrast, high sFOXP3 + TILs was associated with both reduced RFS (e) and OS (f). c Kaplan–Meier survival curves illustrating the relapse-free survival (RFS) and overall survival (OS) according to the ratio of iCD4/CD8 (a, b), iCD8/FOXP3 (c, d) and iFOXP3/CD4 (e, f). d Recurrence-free survival (RFS) and overall survival (OS) in patients with different sCD4/CD8, sCD8/FOXP3, and sFOXP3/CD4 ratios. Estimated Kaplan–Meier curves of RFS (a) and OS (b) in patients with high or low sCD4/CD8 ratios, those of RFS (c) and OS (d) in patients with high or low sCD8/FOXP3 ratios, and those of RFS (e) and OS (f) in patients with high or low sFOXP3/CD4 ratios
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