Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

Abstract

Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.

Expression and clinical implications of estrogen receptors in thoracic malignancies: a narrative review

“…The immunosuppressive properties of estrogens deserve further investigation in NSCLC, because of the importance of immunotherapy in this disease, and the data showing that females do not benefit from immunotherapy treatment as much as men. Despite the recent reports on sex-based differences in the use of immunotherapy in NSCLC patients, current knowledge about the effect of sex hormones on immune function in this context is still in its early stages (54). Actually, even the relationship between the hormone replacement therapy (HRT) and NSCLC is controversial.…”

Plausible Role of Estrogens in Pathogenesis, Progression and Therapy of Lung Cancer

“…Furthermore, one of the treatments for lung cancer may be anti-estrogen therapy. Additionally, 17-β-estradiol is produced by aromatase activity, which in turn influences the control of estrogen levels in the lung cancer microenvironment [ 94 , 95 ]. Clinical studies suggest that aromatase inhibitors are a good therapeutic option for lung adenocarcinoma [ 94 , 96 ].…”

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC)

“…Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancers and has a poor prognosis at later stages [2,3]. The immune system plays an integral role in tumorigenesis and escape from immune surveillance is a recognized feature of cancer [4]. Many new therapeutic strategies have focused on agents that block inhibitory T-cell immune checkpoints, including antibodies toward cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1) [5,6,7].…”