br b UCLA Department of Chemistry and Bi http www
b UCLA Department of Chemistry and Biochemistry, Los Angeles CA 90095, USA
c UCLA Department of Surgery, Division of Surgical Oncology, Los Angeles CA 90095, USA
e UCLA Jonsson Comprehensive Cancer Center, Los Angeles CA 90095, USA
Selective estrogen receptor downregulator
Myeloid-derived suppressor cells
Breast cancers (BCs) with expression of estrogen receptor-alpha (ERα) occur in more than 70% of newly-diag-nosed patients in the U.S. Endocrine therapy with antiestrogens or aromatase inhibitors is an important inter-vention for BCs that express ERα, and it remains one of the most eﬀective targeted treatment strategies. However, a substantial proportion of patients with localized disease, and essentially all patients with metastatic BC, become resistant to current endocrine therapies. ERα is present in most resistant BCs, and in many of these its activity continues to regulate BC growth. Fulvestrant represents one class of ERα antagonists termed selective ER downregulators (SERDs). Treatment with fulvestrant causes ERα down-regulation, an event that helps overcome several resistance mechanisms. Unfortunately, full antitumor eﬃcacy of fulvestrant is limited by its poor bioavailability in clinic. We have designed and tested a new generation of steroid-like SERDs. Using ERα-positive BC LY-500307 in vitro, we find that these compounds suppress ERα protein levels with eﬃcacy similar to fulvestrant. Moreover, these new SERDs markedly inhibit ERα-positive BC cell transcription and proliferation in vitro even in the presence of estradiol-17β. In vivo, the SERD termed JD128 significantly inhibited tumor growth in MCF-7 xenograft models in a dose-dependent manner (P < 0.001). Further, our findings indicate that these SERDs also interact with ER-positive immune cells in the tumor microenvironment such as myeloid-derived suppressor cells (MDSC), tumor infiltrating lymphocytes and other selected immune cell subpopulations. SERD-induced inhibition of MDSCs and concurrent actions on CD8+ and CD4 + T-cells promotes interaction of im-mune checkpoint inhibitors with BC cells in preclinical models, thereby leading to enhanced tumor killing even among highly aggressive BCs such as triple-negative BC that lack ERα expression. Since monotherapy with immune checkpoint inhibitors has not been eﬀective for most BCs, combination therapies with SERDs that enhance immune recognition may increase immunotherapy responses in BC and improve patient survival. Hence, ERα antagonists that also promote ER downregulation may potentially benefit patients who are un-responsive to current endocrine therapies.
Endocrine therapies that target the estrogen receptor (ER) in breast cancer (BC) have significant clinical benefit when used to treat ER-positive tumors and are often an eﬀective targeted treatment for me-tastatic disease. However, a substantial number of patients with
localized disease, and almost all patients with metastatic breast cancer, become resistant to endocrine therapies [1–3]. In the absence of options to current treatments such as antiestrogens (tamoxifen) or aromatase inhibitors (AI), cytotoxic chemotherapy is often the only alternative. Similarly, chemotherapies are often used for patients with triple-nega-tive breast cancer (TNBC). The TNBC subtype occurs in 15–20% of BC
Corresponding author at: UCLA David Geﬀen School of Medicine, Department of Medicine- Hematology/Oncology, 11-934 Factor Building, 700 Tiverton Avenue, Los Angeles, CA 90095-1678, USA.
E-mail address: [email protected] (R.J. Pietras).
1 These authors contributed equally to this work.
patients and cannot be managed with endocrine or HER2-targeted therapies because TNBCs lack ERα and progesterone receptor (PR) expression and have no HER2 overexpression. However, recent clinical trials reveal that 20–30% of TNBC patients respond to immunotherapy such as immune checkpoint inhibitors (ICI) [4,5]. Despite this advance, the great majority of patients with TNBC and other BC subtypes do not benefit from ICI.
In the context of estrogen signaling in BC in vivo, it is important to note that estrogens do not only act directly on BC cells. Rather, it is known that estrogens also regulate the development and function of immune cells that occupy the tumor microenvironment (TME) [6–8]. Despite well-known sex-related diﬀerences in immune responses in various autoimmune diseases , little is known to date about the ef-fect of estrogens or antiestrogens on tumor immune tolerance and im-mune checkpoint blockade in breast cancer. ERα, the major ER form, is known to exhibit high expression in early hematopoietic progenitors in bone marrow such as hematopoietic stem cells and common lymphoid and myeloid progenitors [6–8,10,11]. The programmed death-1 (PD-1) pathway is an immune checkpoint used by many tumor cells to evade detection and attack by tumor-directed T-cells [12–14] that are known to express ER . PD-1 is expressed at the surface of activated T-cells where it interacts with its ligands, such as programmed death ligand-1 (PD-L1), to attenuate T-cell signaling, resulting in downregulation of T-cell proliferation, activation and the antitumor immune response. Al-though PD-L1 is rarely expressed in normal breast tissue, it is expressed in some BC cells and surrounding immune cells where it can mediate inhibition of tumor-infiltrating lymphocytes (TILs) which are a known prognostic indicator for benefit from ICI [15,16].