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Updated: Jan 30, 2026
Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
Published on: March 20, 2020
WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer
Lorenzo Castagnoli1, Valeria Cancila2, Sandra L Cordoba-Romero1
1Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Abstract:
Triple-negative breast cancers (TNBCs) are characterized by a poor prognosis and lack of targeted treatments, and thus, new therapeutic strategies are urgently needed. Inhibitors against programmed death-1 (PD-1)/PD-1 ligand (PD-L1) have shown significant efficacy in various solid cancers, but their activity against TNBCs remains limited. Here, we report that human TNBCs molecularly stratified for high levels of PD-L1 (PD-L1High) showed significantly enriched expression of immune and cancer stemness pathways compared with those with low PD-L1 expression (PD-L1Low). In addition, the PD-L1High cases were significantly associated with a high stemness score (SSHigh) signature. TNBC cell lines gated for aldehyde dehydrogenase (ALDH) and CD44 stemness markers exhibited increased levels of PD-L1 versus their ALDH-negative and CD44Low counterparts, and PD-L1High cells generated significantly more mammospheres than PD-L1Low cells. Murine mammary SCA-1-positive tumor cells with PD-L1High expression generated tumors in vivo with higher efficacy than PD-L1Low cells. Furthermore, treatment of TNBC cells with selective WNT inhibitors or activators downregulated or upregulated PD-L1 expression, respectively, implying a functional cross-talk between WNT activity and PD-L1 expression. Remarkably, human TNBC samples contained tumor elements co-expressing PD-L1 with ALDH1A1 and/or CD44v6. Additionally, both PD-L1-/SCA1-positive and ALDH1A1-positive tumor elements were found in close contact with CD3-, and PD-1-positive T cells in murine and human tumor samples. Overall, our study suggests that PD-L1-positive tumor elements with a stemness phenotype may participate in the complex dynamics of TNBC-related immune evasion, which might be targeted through WNT signaling inhibition.
Insights
Triple-negative breast cancer (TNBC) with high PD-L1 expression shows enriched stemness pathways. Targeting WNT signaling may overcome immune evasion in PD-L1-positive TNBC stem cells.
Area of Science:
- Oncology
- Immunology
- Cancer Stem Cell Biology
Background:
- Triple-negative breast cancer (TNBC) has a poor prognosis and limited targeted therapies.
- Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) inhibitors show efficacy in solid cancers but limited activity in TNBC.
- New therapeutic strategies for TNBC are urgently needed.
Purpose of the Study:
- To investigate the relationship between PD-L1 expression and cancer stemness in TNBC.
- To explore the role of WNT signaling in regulating PD-L1 expression in TNBC.
- To identify potential therapeutic targets for TNBC immune evasion.
Main Methods:
- Molecular stratification of human TNBCs based on PD-L1 expression levels.
- Analysis of immune and cancer stemness pathways in PD-L1-high versus PD-L1-low TNBCs.
- In vitro and in vivo studies using TNBC cell lines and murine models, assessing stemness markers (ALDH, CD44) and PD-L1 expression.
- Investigation of WNT signaling pathway modulation on PD-L1 expression.
- Co-expression analysis of PD-L1, stemness markers, and immune cells in human and murine tumor samples.
Main Results:
- Human TNBCs with high PD-L1 expression (PD-L1High) exhibited enriched immune and cancer stemness pathways compared to PD-L1-low (PD-L1Low) cases.
- PD-L1High TNBCs were significantly associated with a high stemness score (SSHigh).
- TNBC cell lines with stemness markers (ALDH, CD44) showed increased PD-L1 levels and enhanced mammosphere formation.
- PD-L1High murine tumor cells demonstrated higher in vivo tumor-generating efficacy.
- WNT pathway modulation (inhibitors/activators) directly affected PD-L1 expression in TNBC cells, indicating cross-talk.
- Tumor elements co-expressing PD-L1 with stemness markers (ALDH1A1, CD44v6) were found in human TNBC samples.
- PD-L1-positive and stemness-associated tumor elements were in close proximity to T cells (CD3-, PD-1-positive) in both murine and human tumors.
Conclusions:
- PD-L1-positive tumor cells with stemness phenotypes contribute to immune evasion in TNBC.
- A functional link exists between WNT signaling and PD-L1 expression in TNBC.
- Targeting WNT signaling may represent a novel therapeutic strategy to overcome immune evasion in PD-L1-positive, stemness-associated TNBC.
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