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Updated: Jan 29, 2026
Production and Detection of Reactive Oxygen Species ROS in Cancers
Published on: November 21, 2011
Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1
Cecilia Roux1,2, Soode Moghadas Jafari1, Rahul Shinde1
1The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada.
Abstract:
The combination of immune checkpoint blockade with chemotherapy is currently under investigation as a promising strategy for the treatment of triple negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are the most prominent component of the breast cancer microenvironment because they influence tumor progression and the response to therapies. Here we show that macrophages acquire an immunosuppressive phenotype and increase the expression of programmed death ligand-1 (PD-L1) when treated with reactive oxygen species (ROS) inducers such as the glutathione synthesis inhibitor, buthionine sulphoximine (BSO), and paclitaxel. Mechanistically, these agents cause accumulation of ROS that in turn activate NF-κB signaling to promote PD-L1 transcription and the release of immunosuppressive chemokines. Systemic in vivo administration of paclitaxel promotes PD-L1 accumulation on the surface of TAMS in a mouse model of TNBC, consistent with in vitro results. Combinatorial treatment with paclitaxel and an anti-mouse PD-L1 blocking antibody significantly improved the therapeutic efficacy of paclitaxel by reducing tumor burden and increasing the number of tumor-associated cytotoxic T cells. Our results provide a strong rationale for the use of anti-PD-L1 blockade in the treatment of TNBC patients. Furthermore, interrogation of chemotherapy-induced PD-L1 expression in TAMs is warranted to define appropriate patient selection in the use of PD-L1 blockade.
Insights
Chemotherapy and immune checkpoint blockade show promise for triple-negative breast cancer (TNBC). Paclitaxel increases immunosuppressive PD-L1 on macrophages, but combining it with PD-L1 blockade enhances treatment efficacy in TNBC models.
Area of Science:
- Immunology
- Oncology
- Cancer Biology
Background:
- Triple-negative breast cancer (TNBC) is a challenging subtype often treated with chemotherapy and immune checkpoint blockade.
- Tumor-associated macrophages (TAMs) play a critical role in the tumor microenvironment, influencing tumor progression and therapeutic response.
- Programmed death ligand-1 (PD-L1) expression on TAMs can contribute to an immunosuppressive tumor microenvironment.
Purpose of the Study:
- To investigate the effect of chemotherapy, specifically paclitaxel, on TAM phenotype and PD-L1 expression in TNBC.
- To explore the underlying mechanisms of chemotherapy-induced PD-L1 upregulation on TAMs.
- To evaluate the therapeutic potential of combining paclitaxel with PD-L1 blockade in a TNBC mouse model.
Main Methods:
- In vitro treatment of macrophages with reactive oxygen species (ROS) inducers (BSO, paclitaxel).
- Assessment of PD-L1 expression, NF-κB signaling, and chemokine release.
- In vivo studies using a mouse model of TNBC treated with paclitaxel and/or anti-PD-L1 antibody.
- Analysis of tumor burden and tumor-associated cytotoxic T cell infiltration.
Main Results:
- Paclitaxel and BSO induce ROS accumulation, activating NF-κB signaling and increasing PD-L1 expression and immunosuppressive chemokines in macrophages.
- In vivo paclitaxel treatment increases PD-L1 on TAMs in a TNBC mouse model.
- Combination therapy of paclitaxel and anti-PD-L1 antibody significantly reduced tumor burden and increased cytotoxic T cells.
Conclusions:
- Chemotherapy-induced ROS promotes TAM immunosuppression and PD-L1 expression, contributing to immune evasion in TNBC.
- Combining paclitaxel with PD-L1 blockade offers a promising therapeutic strategy for TNBC by overcoming macrophage-mediated immunosuppression.
- Further investigation into chemotherapy-induced PD-L1 expression in TAMs is crucial for optimizing patient selection for PD-L1 blockade therapies.
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