Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells
Huhn, D.; Marti-Rodrigo, P.; Mouron, S.; Hansel, C.; Tschapalda, K.; Haggblad, M.; Lidemalm, L.; Quintela-Fandino, M. A.; Carreras-Puigvert, J.; Fernandez-Capetillo, O.
Show abstract
Estrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ER depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.
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