TIM3 expression on TILs is associated with poor response to neoadjuvant chemotherapy in patients with locally advanced triple-negative breast cancer

BMC Cancer. 2021 Apr 6;21(1):357. doi: 10.1186/s12885-021-08054-6.


Background: The expression of immune checkpoint receptors (ICRs) on tumor-infiltrating lymphocytes (TILs) is associated with better response to immunotherapies via immune checkpoint inhibitors. Therefore, we investigated various ICR expressions on TILs in patients with locally advanced triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC).

Methods: Expressions of ICRs were examined immunohistochemically in surgical specimens (n = 61) using monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, and CTLA-4. Positivity was defined as staining > 1% on TILs.

Results: The median age was 49 (24-76) years. The majority of patients were clinically T3-4 (n = 31, 50.8%) and clinically N1-3 (n = 58, 95.1%) before NAC. Of those, 82% were found to have CTLA-4 positivity, whereas PD1, PDL-1, LAG3, and TIM-3 expressions on TILs were 62.3, 50.9, 26.2, and 68.9%. A high expression of CTLA-4 was found to be associated with a better chemotherapy response (OR = 7.94, 95% CI: 0.9-70.12, p = 0.06), whereas TIM-3 positivity was contrarily associated with a worse chemotherapy response (OR = 0.253, 95% CI: 0.066-0.974, p = 0.047) as measured by the MDACC Residual Cancer Burden Index. At a 47-month follow-up, ypN0 (DFS; HR = 0.31, 95% CI: 0.12-0.83, p = 0.02 and DSS; HR = 0.21, 95% CI: 0.07-0.62, p = 0.005) and CTLA-4 high expression on TILs (DFS; HR = 0.38, 95% CI: 0.17-0.85, p = 0.019 and DSS; HR = 0.34, 95% CI: 0.15-0.78, p = 0.01) were found to be associated with improved survival.

Conclusions: These findings demonstrate that CTLA-4, PD-1, PDL-1, and TIM-3 were highly expressed in TNBC. Based on these high expression patterns, further studies directed towards combined therapies are warranted in advanced TNBC in future.

Keywords: CTLA4; LAG-3; Mucin domain-containing molecule 3 (TIM3); PD1; PDL1; T-cell immunoglobulin; Triple negative breast cancer; Tumor infiltrating lymphocytes (TILs).

MeSH terms

  • Adult
  • Aged
  • Female
  • Hepatitis A Virus Cellular Receptor 2 / metabolism*
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Middle Aged
  • Neoadjuvant Therapy / methods*
  • Triple Negative Breast Neoplasms / genetics*
  • Young Adult


  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2