Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells
Daniela Hühn1, Pablo Martí-Rodrigo1, Silvana Mouron2
1Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
Abstract:
Among others, expression levels of programmed cell death 1 ligand 1 (PD-L1) have been explored as biomarkers of the response to immune checkpoint inhibitors in cancer therapy. Here, we present the results of a chemical screen that interrogated how medically approved drugs influence PD-L1 expression. As expected, corticosteroids and inhibitors of Janus kinases were among the top PD-L1 downregulators. In addition, we identified that PD-L1 expression is induced by antiestrogenic compounds. Transcriptomic analyses indicate that chronic estrogen receptor alpha (ERα) inhibition triggers a broad immunosuppressive program in ER-positive breast cancer cells, which is subsequent to their growth arrest and involves the activation of multiple immune checkpoints together with the silencing of the antigen-presenting machinery. Accordingly, estrogen-deprived MCF7 cells are resistant to T-cell-mediated cell killing, in a manner that is independent of PD-L1, but which is reverted by estradiol. Our study reveals that while antiestrogen therapies efficiently limit the growth of ER-positive breast cancer cells, they concomitantly trigger a transcriptional program that favors their immune evasion.
Insights
Antiestrogenic compounds induce programmed cell death 1 ligand 1 (PD-L1) expression, promoting immune evasion in estrogen receptor-positive breast cancer. This contrasts with corticosteroids and Janus kinase inhibitors, which downregulate PD-L1.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Programmed cell death 1 ligand 1 (PD-L1) expression is a key biomarker for immune checkpoint inhibitor therapy response in cancer.
- Understanding how medically approved drugs affect PD-L1 levels is crucial for optimizing cancer treatment strategies.
Purpose of the Study:
- To investigate the impact of medically approved drugs on PD-L1 expression.
- To identify novel regulators of PD-L1 expression and their downstream effects on immune evasion in breast cancer.
Main Methods:
- Chemical screening of medically approved drugs for their effect on PD-L1 expression.
- Transcriptomic analysis to elucidate the molecular mechanisms underlying PD-L1 regulation.
- Assessment of T-cell-mediated cytotoxicity in drug-treated cancer cells.
Main Results:
- Corticosteroids and Janus kinase inhibitors were confirmed as PD-L1 downregulators.
- Antiestrogenic compounds were identified as novel inducers of PD-L1 expression.
- Estrogen receptor alpha (ERα) inhibition in ER-positive breast cancer cells led to broad immunosuppression, immune checkpoint activation, and impaired antigen presentation, resulting in T-cell resistance.
- Estradiol treatment reverted the observed T-cell resistance.
Conclusions:
- While antiestrogen therapies inhibit ER-positive breast cancer cell growth, they concurrently induce an immune-evasive transcriptional program.
- These findings highlight a critical interplay between hormonal therapy and immune response in breast cancer, suggesting potential therapeutic strategies to overcome immune evasion.
