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.
Highlights
The high incidence and mortality rate of lung cancer represents a global health problem
We summarize below the established correlation between pharmacologic hormonal modulation (though hormone replacement therapy (HRT) or antiestrogen treatment in breast cancer patient cohorts) and non-small cell lung carcinoma (NSCLC) incidence, the prognostic value of hormonal markers in NSCLC patient tumors, and completed or ongoing clinical trials testing agents that target estrogen signaling for NSCLC patients
Results from the Women’s Health Initiative (WHI) randomized, double blind controlled trial conducted with the goal of determining the effects of hormone replacement therapy (HRT) on postmenopausal women (n = 10,739) who were prescribed estrogen and progesterone (E+P) to mitigate the symptoms of menopause, found that the women taking E+P had an increase in lung cancer mortality [69]
Summary
The high incidence and mortality rate of lung cancer represents a global health problem. In a meta-analysis of 20 Phase II and III RCTs that included over 11,000 advanced cancer patients, including NSCLC, a statistically significant difference in efficacy between male and female patients treated with CTLA-4 or PD-1/PDL-1 blocking antibodies compared to standard of care treatment was observed (P = 0.0019) [47]. While both male and female patients showed reduced risk of death with ICI, the benefit for females was not as strong as for males. One potential mechanism for the increased benefit from combined chemotherapy and ICI treatment in females is the ability of chemotherapy to increase the mutational burden and tumor antigen release into the microenvironment, leading to mitigation of immunosuppressive effects
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