Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3
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Updated: Nov 13, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
Shafei Wu1, Xiaohua Shi1, Jing Wang1
1Department of Pathology, Peking Union Medical College Hospital, Molecular Pathology Research Center, Chinese Academy of Medical Sciences, Beijing, China.
Background And Aim:
Poor response to immune checkpoint inhibitors (ICIs) has been observed in most triple-negative breast cancer (TNBC) cases (around 80%). Our aim was to investigate the status of mismatch repair (MMR), microsatellite instability (MSI), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) in TNBC.
Methods:
A total of 74 TNBC samples were retrospectively analyzed. MMR and MSI were evaluated by immunohistochemistry (IHC) and polymerase chain reaction (PCR) using Promega 1.2 and NCI panels, respectively. PD-L1, LAG-3, and CD8 expression was assessed by IHC.
Results:
None of the cases demonstrated deficient MMR (dMMR) or MSI. In total, 43/74 cases (58.1%) were PD-L1+, including 1 tumor PD-L1+, 25 tumor-infiltrating lymphocytes (TILs) PD-L1+, and 17 cases involving concurrence of tumor and TIL PD-L1+. The rate of TIL PD-L1+ was remarkably higher than that of tumor PD-L1+ (P<0.001). We identified 20 LAG-3+ cases (27.0%, 20/74), all of which were PD-L1+. Co-expression of PD-L1 and LAG-3 was noted in 46.5% (20/43) of the PD-L1+ population. In the LAG-3+ subtype (co-expression of PD-L1 and LAG-3), high correlation between TILs PD-L1+ and LAG-3+ was observed (P<0.01). A high frequency of CD8+ (98.6%, 73/74) was observed.
Conclusion:
dMMR/MSI characteristics may not be a practical predictive marker for ICIs in TNBC. PD-L1+ is more common in TILs than in tumors. In the PD-L1+ population, approximately half of the cases showed LAG-3 co-expression. For patients with a poor response to PD-1(L1) mono ICI, dual blockade of PD-1(L1) and LAG-3 may be a viable option for the management of TNBC.
Insights
Most triple-negative breast cancer (TNBC) patients do not respond to immune checkpoint inhibitors (ICIs). PD-L1 expression is more common in tumor-infiltrating lymphocytes (TILs) than tumors, and LAG-3 co-expression suggests dual blockade therapy may benefit patients.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Triple-negative breast cancer (TNBC) exhibits poor response rates to immune checkpoint inhibitors (ICIs), affecting approximately 80% of cases.
- Investigating biomarkers such as mismatch repair (MMR), microsatellite instability (MSI), programmed death-ligand 1 (PD-L1), and lymphocyte-activation gene 3 (LAG-3) is crucial for understanding ICI efficacy in TNBC.
Purpose of the Study:
- To evaluate the expression status of MMR, MSI, PD-L1, and LAG-3 in TNBC samples.
- To determine the clinical relevance of these markers in predicting response to ICIs.
Main Methods:
- Retrospective analysis of 74 TNBC samples.
- MMR and MSI assessment using immunohistochemistry (IHC) and polymerase chain reaction (PCR).
- PD-L1, LAG-3, and CD8 expression analysis via IHC.
Main Results:
- No TNBC cases showed deficient MMR (dMMR) or MSI.
- PD-L1 positivity was observed in 58.1% of cases, with significantly higher prevalence in tumor-infiltrating lymphocytes (TILs) compared to tumor cells (P<0.001).
- LAG-3 was detected in 27.0% of cases, exclusively in PD-L1+ samples, with co-expression observed in 46.5% of the PD-L1+ population. High CD8+ T-cell infiltration was noted in 98.6% of cases.
Conclusions:
- dMMR/MSI are unlikely to be predictive markers for ICI therapy in TNBC.
- PD-L1 expression is predominantly found in TILs rather than tumor cells.
- The high rate of PD-L1 and LAG-3 co-expression suggests that dual PD-1/L1 and LAG-3 blockade could be a promising therapeutic strategy for TNBC patients with poor response to PD-1/L1 monotherapy.
