Targeting Estrogen Receptor Signaling with Fulvestrant Enhances Immune and Chemotherapy-Mediated Cytotoxicity of Human Lung Cancer

Abstract

Purpose The conversion of tumor cells from an epithelial to a mesenchymal-like phenotype, via a process designated as the epithelial-mesenchymal transition (EMT), is known to mediate tumor resistance to a variety of cell death inducers, including cytotoxic effector immune cells. The goal of this study was to identify and potentially repurpose FDA-approved compounds capable of reducing mesenchymal features of human lung carcinoma cells, which could be used in combination with immunotherapies or chemotherapeutic strategies to improve clinical responses. Experimental Design In the present report we have utilized a quantitative high throughput screening (qHTS) of a pharmaceutical collection of more than 2,000 compounds to identify clinically approved drugs capable of augmenting the sensitivity of mesenchymal-like, lung cancer cells to immune- and chemotherapy-mediated lysis, both in vitro and in vivo. Results The estrogen receptor antagonist fulvestrant was shown to reduce mesenchymal features of lung carcinoma cells, resulting in tumor sensitization to the cytotoxic effect of antigen-specific T cells, natural killer (NK) effectors cells and chemotherapy both in vivo and in vitro. Conclusions To our knowledge, this is the first report defining a potential role for estrogenic signaling in promoting tumor resistance to immune-mediated cytotoxicity and chemotherapy in lung cancer. Our data demonstrates a robust association between the acquisition of mesenchymal attributes, therapeutic resistance of lung carcinoma cells, and the expression of estrogen receptor 1 (ESR1), supporting further investigations on the role of estrogen signaling in lung cancer progression via the induction of EMT.

Neutralization of IL-8 decreases tumor PMN-MDSCs and reduces mesenchymalization of claudin-low triple-negative breast cancer

“…Mesenchymalization and the molecular drivers of the process, including the transcription factors Snail, Slug, Twist, and brachyury, have been linked to advanced tumor stage (36)(37)(38), presence of metastases (39), and poor prognosis in numerous cancer types (40)(41)(42). Additionally, mesenchymalization has been associated with resistance to anticancer therapies, including chemotherapy (43,44), small-molecule-targeted therapies (45,46), and to lysis by immune effector cells (47)(48)(49)(50). In the case of breast cancer, this phenomenon has been linked to tumor progression in preclinical models (51) and with patient tumor samples (52,53).…”

New insights into the role of EMT in tumor immune escape

“…who demonstrated that high levels of the EMT‐related factor Brachyury reduced the susceptibility of carcinoma cells not only to CTLs, but also to NK cells, lymphokine‐activated killer, FAS, and TRAIL‐induced cell death. In a recent report investigating the lung cancer setting, the same group further found a potential role for estrogen receptor α in promoting both Mes characteristics and resistance to immune‐mediated cytotoxicity (Hamilton et al ., ). By contrast, the study of López‐Soto et al .…”

“…Recent reports suggested that two widely used compounds, the EGFR inhibitor erlotinib, and fulvestrant, an antagonist of ER, may be efficient at decreasing Mes features of lung cancer cells as well as for improving their lysis by the immune effector cells (Dominguez et al ., ; Hamilton et al ., ). In addition, as suggested in our previous studies, it could be interesting to target autophagy when Mes carcinoma cells exhibit an autophagic state (Akalay et al ., ).…”

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury

“…This dose-escalation phase I study was conducted to demonstrate the safety of MVA-brachyury-TRICOM and to determine its ability to generate brachyury-specific CD4 + or CD8 + T cells in patients with advanced cancer. Future phase II studies of this vaccine will be based on the preclinical rationale of vaccine studies in combination with checkpoint inhibitor monoclonal antibodies (MAbs), immune modulators, inhibitors of immune entities, and combinations of these (6,39–43). …”