Impact of PD‑L1 upregulation on immune checkpoint inhibitor efficacy in triple‑negative breast cancer using a 4T1 murine model

Park,A. Young; Kim,Ju Hee; Lee,Sangeun; Kim,Hoe Suk; Kim,Hong Kyu; Lee,Han-Byoel; Han,Wonshik

doi:10.3892/ijo.2025.5760

Impact of PD‑L1 upregulation on immune checkpoint inhibitor efficacy in triple‑negative breast cancer using a 4T1 murine model

Authors:
- A. Young Park
- Ju Hee Kim
- Sangeun Lee
- Hoe Suk Kim
- Hong Kyu Kim
- Han-Byoel Lee
- Wonshik Han
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Affiliations: Cancer Research Institute, Seoul National University, Seoul 03080, Republic of Korea
Published online on: June 11, 2025 https://doi.org/10.3892/ijo.2025.5760
Article Number: 54
Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Triple‑negative breast cancer (TNBC) is a lethal subtype of breast cancer with a poor prognosis and limited existing treatment options. The immune checkpoint inhibitor, anti‑programmed death ligand 1 (PD‑L1), has recently emerged as a promising alternative in treating TNBC. PD‑L1 is critical in tumor immune evasion and is therefore a key target for cancer immunotherapy. Although anti‑PD‑L1 therapy is effective in breast cancer based on clinical trials, the relationship between PD‑L1 expression levels and treatment response remains unclear. To investigate this, a 4T1 breast cancer cell line that stably overexpressed PD‑L1 was established and was used to create a tumor model in mice. Mice were treated with anti‑PD‑L1 antibodies, and tumor growth was compared between the control and treated groups. PD‑L1 overexpressing tumors did not exhibit an antitumor response to anti‑PD‑L1 therapy compared with the control tumors. Additionally, immune cell infiltration and activation were significantly altered, as shown by immunohistochemical staining and bulk RNA sequencing. In PD‑L1‑overexpressing tumors that did not respond to treatment, immune cell markers and antitumor immune pathways were downregulated. These results demonstrated that excessive PD‑L1 expression creates an immunosuppressive tumor microenvironment, which impairs the efficacy of anti‑PD‑L1 therapy. The present study suggests that excessive PD‑L1 expression reduces the effectiveness of antitumor immunotherapy, and that PD‑L 1 expression levels are essential in predicting the response to antitumor immunotherapy.

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