Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

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 ERa 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.

The immunomodulatory effects of endocrine therapy in breast cancer

“…These discrepancies may be attributable to the different regimens used, suggesting the need for studies with more samples and corresponding pathological assessment. In addition, ER + BC cells grown under estrogen-free conditions presented an upregulation of PD-L1 as a result of ERα signaling abrogation [81], corroborating the possibility of combining NET with immunotherapy in ER + BC.…”

“…In addition, Joffroy et al [12] found that tamoxifen-or fulvestrant-induced TGFβ production in MCF-7 cells led to a decreased cytotoxic effect of CD8 + T cells as well as an increased polarization of CD4 + T cells into Foxp3 + Tregs, which futher supported the development of endocrine resistance. Moreover, ERα signaling blockade or depletion by tamoxifen or fulvestrant evoked the upregulation of programmed deathligand 1 (PD-L1) in multiple ER + BC cell lines, contributing to the cytotoxic T cell evasion of BC cells [81]. The inverse correlation between ERα and PD-L1 was confirmed not only in the MMTV-PyMT transgenic mouse model [81] but also in human BC specimens, where the ratio of PD-L1 positive patients was much lower in ER+/HER2− BC (19.4%) than in triple-negative breast cancer (TNBC, 58.6%) [82,83].…”

“…Moreover, ERα signaling blockade or depletion by tamoxifen or fulvestrant evoked the upregulation of programmed deathligand 1 (PD-L1) in multiple ER + BC cell lines, contributing to the cytotoxic T cell evasion of BC cells [81]. The inverse correlation between ERα and PD-L1 was confirmed not only in the MMTV-PyMT transgenic mouse model [81] but also in human BC specimens, where the ratio of PD-L1 positive patients was much lower in ER+/HER2− BC (19.4%) than in triple-negative breast cancer (TNBC, 58.6%) [82,83]. To summarize, SERMs or SERDs mediate immunosuppressive effects in a direct or indirect manner and protect tumors from immune surveillance, which may decrease their therapeutic effects and result in the development of treatment resistance.…”

Immunotherapy: A Challenge of Breast Cancer Treatment

“…Since estrogen presence in tumor microenvironment can also play a significant immunosuppressive role by promoting tolerance of weakly immunogenic tumor cells [69], the use of antiestrogen therapies in combination with aromatase inhibitors could be a rational strategy to enhance the response to immunotherapies. However, although adjuvant hormonal therapy combined with HER2-targeted agents in hormone receptor-positive and HER2-positive breast cancer patients already represents a standard treatment, recent studies have shown that estrogen deprivation promotes transcriptional programs that favor immune evasion and increases PD-L1 expression in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease [85]. For this reason, the use of hormone-therapies in combination with PD-1/PD-L1 blocking immunotherapies should be thoroughly investigated.…”

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

“…ER-α regulates gene transcription through the direct binding of the receptor to regulatory regions (enhancers or silencers) of target genes [56]. The relationship between ER-α and PD-L1 has been cemented in a study that revealed estrogen deprivation or ER-α depletion induced PD-L1 expression in ER+ breast cancer in vitro and in vivo [66]. While acknowledging how the regulation of IC molecular expression occurs in a bidirectional manner, we propose the master regulators of ICs as the transcription factors located at a hub of a regulatory network or as the direct transcriptional regulator responsible for the gene expression of co-inhibitory (or co-stimulatory) ICs.…”