Abstract
Background and AimPoor 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.MethodsA 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.ResultsNone 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.ConclusiondMMR/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.
Highlights
Breast cancer (BC) is a heterogeneous disease
Based on the findings described, examination of the lymphocyte-activation gene 3 (LAG-3) expression and co-expression of Programmed death-ligand 1 (PD-L1) as well as elucidation of the tumor microenvironment referring to immunotherapeutic resistance to anti-programmed cell death 1 (PD-1)(L1) were all extremely valuable for adopting suitable immunologic treatment and improving the clinical effect of anti-PD-1(L1) therapy in triple-negative breast cancer (TNBC)
According to the manufacturer’s protocols, primary monoclonal antibodies against MLH1, MSH2, MSH6, and PMS2 were used based on Ventana BenchMark autostainer (Ventana Medical System, Inc., Tucson, AZ, USA). deficient mismatch repair (dMMR) was considered when any of the four mismatch repair (MMR) proteins were completely absent in the nuclear staining of tumor tissue, while concurrent positive benign cells were found in adjacent tissues, and intact IHC staining of these four antibodies was classified as proficient MMR according to the interpretation criteria described previously [21]
Summary
Breast cancer (BC) is a heterogeneous disease. Molecular types, essentially including luminal, human epidermal growth factor receptor 2 positive (HER2+), and triple-negative, for which clinical outcomes are closely tied to the corresponding treatment, are categorized based on the status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). The prognosis of triple-negative breast cancer (TNBC) is relatively poor, and the tumors recur rapidly [1,2,3]. Programmed death-ligand 1 (PD-L1), which is a negative regulator of T-cell activation, is expressed in many cancers. The interaction of programmed cell death 1 (PD-1) and its ligand, PD-L1, is known to act as a critical blockade pathway in malignant tumors for regulating immune escape. 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
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