Dataset Information

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3.

ABSTRACT:

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.

SUBMITTER: Wu S

PROVIDER: S-EPMC7943629 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3.

Wu Shafei S Shi Xiaohua X Wang Jing J Wang Xuefei X Liu Yuanyuan Y Luo Yufeng Y Mao Feng F Zeng Xuan X

Frontiers in immunology 20210224

<h4>Background and aim</h4>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.<h4>Methods</h4>A total of 74 TNBC samples were retrospectively analyzed. MMR and MSI were evaluated by immunohistochemistry (IHC) and polymerase chain rea ...[more]

PMID: 33717059

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Project description:(1) Background: Triple-negative breast cancer (TNBC) is a distinct subgroup of breast cancer presenting a high level of recurrence, and neo-adjuvant chemotherapy is beneficial in its therapy management. Anti-PD-L1 immunotherapy improves the effect of neo-adjuvant therapy in TNBC. (2) Methods: Immune-modulation and ferroptosis-related R-packages were developed for integrative omics analyses under ferroptosis-inducer treatments: TNBC cells stimulated with ferroptosis inducers (GSE173905, GSE154425), single cell data (GSE191246) and mass spectrometry on breast cancer stem cells. Clinical association analyses were carried out with breast tumors (TCGA and METABRIC cohorts). Protein-level validation was investigated through protein atlas proteome experiments. (3) Results: Erastin/RSL3 ferroptosis inducers upregulate CD274 in TNBC cells (MDA-MB-231 and HCC38). In breast cancer, CD274 expression is associated with overall survival. Breast tumors presenting high expression of CD274 upregulated some ferroptosis drivers associated with prognosis: IDO1, IFNG and TNFAIP3. At the protein level, the induction of Cd274 and Tnfaip3 was confirmed in breast cancer stem cells under salinomycin treatment. In a 4T1 tumor treated with cyclophosphamide, the single cell expression of Cd274 was found to increase both in myeloid- and lymphoid-infiltrated cells, independently of its receptor Pdcd1. The CD274 ferroptosis-driver score computed on a breast tumor transcriptome stratified patients on their prognosis: low score was observed in the basal subgroup, with a higher level of recurrent risk scores (oncotypeDx, ggi and gene70 scores). In the METABRIC cohort, CD274, IDO1, IFNG and TNFAIP3 were found to be overexpressed in the TNBC subgroup. The CD274 ferroptosis-driver score was found to be associated with overall survival, independently of TNM classification and age diagnosis. The tumor expression of CD274, TNFAIP3, IFNG and IDO1, in a biopsy of breast ductal carcinoma, was confirmed at the protein level (4) Conclusions: Ferroptosis inducers upregulate PD-L1 in TNBC cells, known to be an effective target of immunotherapy in high-risk early TNBC patients who received neo-adjuvant therapy. Basal and TNBC tumors highly expressed CD274 and ferroptosis drivers: IFNG, TNFAIP3 and IDO1. The CD274 ferroptosis-driver score is associated with prognosis and to the risk of recurrence in breast cancer. A potential synergy of ferroptosis inducers with anti-PD-L1 immunotherapy is suggested for recurrent TNBC.

Project description:Immunotherapies have led to substantial changes in cancer treatment and have been a persistently popular topic in cancer research because they tremendously improve the efficacy of treatment and survival of individuals with various cancer types. However, only a small proportion of patients are sensitive to immunotherapy, and specific biomarkers are urgently needed to separate responders from nonresponders. Mismatch repair pathways play a vital role in identifying and repairing mismatched bases during DNA replication and genetic recombination in normal and cancer cells. Defects in DNA mismatch repair proteins and subsequent microsatellite instability-high lead to the accumulation of mutation loads in cancer-related genes and the generation of neoantigens, which stimulate the anti-tumor immune response of the host. Mismatch repair deficiency/microsatellite instability-high represents a good prognosis in early colorectal cancer settings without adjuvant treatment and a poor prognosis in patients with metastasis. Several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors. To date, the anti-programmed cell death-1 inhibitor pembrolizumab has been approved for mismatch repair deficiency/microsatellite instability-high refractory or metastatic solid tumors, and nivolumab has been approved for colorectal cancer patients with mismatch repair deficiency/microsatellite instability-high. This is the first time in the history of cancer therapy that the same biomarker has been used to guide immune therapy regardless of tumor type. This review summarizes the features of mismatch repair deficiency/microsatellite instability-high, its relationship with programmed death-ligand 1/programmed cell death-1, and the recent advances in predicting immunotherapy efficacy.

Dataset Information

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3.

Background and aim

Methods

Results

Conclusion

Publications

Triple-Negative Breast Cancer: Intact Mismatch Repair and Partial Co-Expression of PD-L1 and LAG-3.

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