J Breast Cancer.  2018 Dec;21(4):406-414. 10.4048/jbc.2018.21.e61.

T-Cell Immunoglobulin Mucin 3 Expression on Tumor Infiltrating Lymphocytes as a Positive Prognosticator in Triple-Negative Breast Cancer

Affiliations
  • 1Department of Surgery, Dong-A University College of Medicine, Busan, Korea.
  • 2Breast Medical Center, Dong-A University College of Medicine, Busan, Korea.
  • 3Department of Pathology, Dong-A University College of Medicine, Busan, Korea. jsjung1@dau.ac.kr
  • 4Department of Radiology, Dong-A University College of Medicine, Busan, Korea.

Abstract

PURPOSE
T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is an emerging immune response molecule related to T-cell anergy. There has been tremendous interest in breast cancer targeting immune checkpoint molecules, especially in the triple-negative breast cancer (TNBC). This study was designed to investigate TIM-3 expression on tumor infiltrating lymphocytes (TILs), its relationships with clinicopathological para-meters and expression of programmed death receptor 1 (PD-1)/programmed death receptor ligand 1 (PD-L1), and its prognostic role.
METHODS
Immunohistochemistry on tissue microarray blocks produced from 109 samples of invasive ductal carcinoma type TNBC was performed with antibodies toward TIM-3, PD-1, PD-L1 and breast cancer-related molecular markers. Associations between their expression and clinicopathological parameters as well as survival analyses were performed.
RESULTS
TIM-3 was expressed in TILs from all 109 TNBCs, consisting of 17 cases ( < 5%), 31 cases (6%-25%), 48 cases (26%-50%), and 13 cases (>51%). High TIM-3 was significantly correlated with younger patients (p=0.0101), high TILs (p=0.0029), high tumor stage (p=0.0018), high PD-1 (p=0.0001) and high PD-L1 (p=0.0019), and tended to be associated with higher histologic grade, absence of extensive in situ components and microcalcification. High TIM-3 expression was significantly associated with a combinational immunophenotype group of high PD-L1 and high PD-1 (p < 0.0001). High TIM-3 demonstrated a significantly better disease-free survival (DFS) (p < 0.0001) and longer overall survival (OS) (p=0.0001), together with high TILs and high PD-1. In univariate survival analysis, high TIM-3 showed reduced relapse risk (p < 0.0001) and longer OS (p=0.0003), together with high PD-1 expression. In multivariate analysis, high TIM-3 was statistically significant in predicting prognosis, showing better DFS (hazard ratio [HR], 0.0994; 95% confidence interval [CI], 0.0296-0.3337; p=0.0002) and longer OS (HR, 0.1109; 95% CI, 0.0314-0.3912; p=0.0006).
CONCLUSION
In this study, we demonstrate that TIM-3 expression is an independent positive prognostic factor in TNBC, despite its association with poor clinical and pathologic features.

Keyword

Prognosis; T-cell immunoglobulin and mucin domain-containing molecule 3; Triple-negative breast neoplasms; Tumor infiltrating lymphocytes
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