Role of sex and sex hormones in PD-L1 expression in NSCLC: clinical and therapeutic implications.

Currently, immunotherapy based on PD-1/PD-L1 pathway blockade has improved survival of non-small cell lung cancer (NSCLC) patients. However, differential responses have been observed by sex, where men appear to respond better than women. Additionally, adverse effects of immunotherapy are mainly observed in women. Studies in some types of hormone-dependent cancer have revealed a role of sex hormones in anti-tumor response, tumor microenvironment and immune evasion. Estrogens mainly promote immune tolerance regulating T-cell function and modifying tumor microenvironment, while androgens attenuate anti-tumor immune responses. The precise mechanism by which sex and sex hormones may modulate immune response to tumor, modify PD-L1 expression in cancer cells and promote immune escape in NSCLC is still unclear, but current data show how sexual differences affect immune therapy response and prognosis. This review provides update information regarding anti-PD-1/PD-L immunotherapeutic efficacy in NSCLC by sex, analyzing potential roles for sex hormones on PD-L1 expression, and discussing a plausible of sex and sex hormones as predictive response factors to immunotherapy.

An Overview of Lung Cancer in Women and the Impact of Estrogen in Lung Carcinogenesis and Lung Cancer Treatment.

Lung cancer incidence and mortality have significantly increased in women worldwide. Lung adenocarcinoma is the most common form of lung cancer globally. This type of lung cancer shows differences by sex, including the mutational burden, behavior, clinical characteristics, and response to treatment. The effect of sex on lung cancer patients' survival is still controversial; however, lung adenocarcinoma is considered a different disease in women and men. Moreover, lung adenocarcinoma is strongly influenced by estrogen and is also different depending on the hormonal status of the patient. Young pre-menopausal women have been explored as an independent group. They presented in more advanced stages at diagnosis, exhibited more aggressive tumors, and showed poor survival compared to men and post-menopausal women, supporting the role of sex hormones in this pathology. Several reports indicate the estrogen's role in lung carcinogenesis and tumor progression. Thus, there are currently some clinical trials testing the efficacy of antihormonal therapy in lung cancer treatment. This mini review shows the updated data about lung cancer in women, its characteristics, the etiological factors that influence carcinogenesis, and the critical role of estrogen in lung cancer and treatment.

Characteristics of non-small cell lung cancer: differences by sex and hormonal status in a Mexican population.

OBJECTIVE: To analyze the differences in the clinico-pathological and molecular characteristics of non-small cell lung cancer (NSCLC) as well as the clinical outcome of patients by sex and hormonal status. MATERIALS AND METHODS: We performed a retrospective study among 1 104 NSCLC patients. Clinic-pathologic data was recorded and survival outcomes were compared between male and female sex patients, and further by pre and postmenopausal status in females. RESULTS: Women were significantly more likely to be non-smokers (p<0.001), had higher frequency of wood-smoke exposure (p<0.001), EGFR-sensitizing mutations (p<0.001), had better performance status (p=0.020) and had a better overall survival (OS) compared to men (p=0.021). Differences were found also by hormonal status, postmenopausal women had a longer OS compared to premenopausal women (31.1 vs. 19.4 months p=0.046).

OBJETIVO: Analizar las diferencias en las características clínico-patológicas, moleculares y en la evolución del cáncer de pulmón de células no pequeñas (CPCNP) por sexo y estadio hormona. MATERIAL Y MÉTODOS: Estudio retrospectivo (N=1 104) en pacientes con CPCNP. Se recabaron datos clínico-patológicos y desenlaces de sobrevida y se compararon entre hombres y mujeres, y entre mujeres pre y postmenopáusicas. RESULTADOS: . Las mujeres de este estudio tuvieron significativamente mayor probabilidad de ser no fumadoras (p<0.001), tener exposición a humo de leña (p<0.001), mutaciones en EGFR (p<0.001), mejor estado funcional (p=0.020), y una mejor sobrevida global (SG) en comparación con los hombres (p=0.021). Estas diferencias también se encontraron en cuestión al estatus hormonal, con las mujeres postmenopáusicas presentando una mayor sobrevida en comparación con las premenopáusicas (31.1 vs.19.4 meses; p=0.046). CONCLUSIONES: Los presentes resultados apoyan las diferencias en la presentación del CPCNP de acuerdo con el sexo y estatus hormonal.

Characteristics of non-small cell lung cancer: differences by sex and hormonal status in a Mexican population / Características del cáncer de pulmón de células no pequeñas: diferencias por sexo y estado hormonal en una población mexicana

Abstract: Objective: To analyze the differences in the clinico-pathological and molecular characteristics of non-small cell lung cancer (NSCLC) as well as the clinical outcome of patients by sex and hormonal status. Materials and methods: We performed a retrospective study among 1 104 NSCLC patients. Clinic-pathologic data was recorded and survival outcomes were compared between male and female sex patients, and further by pre and postmenopausal status in females. Results: Women were significantly more likely to be non-smokers (p<0.001), had higher frequency of wood-smoke exposure (p<0.001), EGFR-sensitizing mutations (p<0.001), had better performance status (p=0.020) and had a better overall survival (OS) compared to men (p=0.021). Differences were found also by hormonal status, postmenopausal women had a longer OS compared to premenopausal women (31.1 vs. 19.4 months p=0.046). Conclusion: Our results support the differences in lung cancer presentation by sex and also by hormonal status.

Resumen: Objetivo: Analizar las diferencias en las características clínico-patológicas, moleculares y en la evolución del cáncer de pulmón de células no pequeñas (CPCNP) por sexo y estadio hormonal. Material y métodos: Estudio retrospectivo (N=1 104) en pacientes con CPCNP. Se recabaron datos clínico-patológicos y desenlaces de sobrevida y se compararon entre hombres y mujeres, y entre mujeres pre y postmenopáusicas. Resultados: Las mujeres de este estudio tuvieron significativamente mayor probabilidad de ser no fumadoras (p<0.001), tener exposición a humo de leña (p<0.001), mutaciones en EGFR (p<0.001), mejor estado funcional (p=0.020), y una mejor sobrevida global (SG) en comparación con los hombres (p=0.021). Estas diferencias también se encontraron en cuestión al estatus hormonal, con las mujeres postmenopáusicas presentando una mayor sobrevida en comparación con las premenopáusicas (31.1 vs. 19.4 meses; p=0.046). Conclusión: Los presentes resultados apoyan las diferencias en la presentación del CPCNP de acuerdo con el sexo y estatus hormonal.

Influence of estrogen in non-small cell lung cancer and its clinical implications.

Lung cancer (LC) is the leading cause of cancer death in men worldwide and has significantly increased in women. Differences in non-small cell lung cancer (NSCLC) behavior, prognosis, and response to treatment have been reported by sex and hormonal status, with premenopausal women presenting the worst prognosis compared to postmenopausal women and men. Additionally, the use of hormonal replacement therapy significantly increases NSCLC mortality; supporting the role of estrogen signaling in the pathogenesis of LC. The mechanisms by which estrogen promotes lung carcinogenesis have not been fully elucidated. Estrogen, through its receptor, can stimulate LC cell proliferation, death resistance, angiogenesis, migration and metastasis. Estrogen also induces expression of pro-inflammatory proteins and ligands that promote tumor evasion, suggesting that estrogen might modify the microenvironment and anti-tumor immune response. Recent reports have shown an interaction between the epidermal growth factor receptor (EGFR) pathway and estrogen signaling in lung adenocarcinoma, whence, combined treatment based on tyrosine kinase inhibitors (TKIs) and antiestrogen therapy is beginning to be evaluated. This review focuses on the differences in NSCLC behavior by sex and hormonal status, highlighting the role of estrogen and its receptors in lung carcinogenesis and LC prognosis. Due to the importance of estrogen in NSCLC development and progression we finally discuss the potential of antiestrogen therapy in LC treatment and show the results from preclinical and clinical trials.

Estrogen induces CXCR4 overexpression and CXCR4/CXL12 pathway activation in lung adenocarcinoma cells in vitro.

PURPOSE: This study was designed to investigate whether estradiol is related to the expression of the chemokine receptor CXCR4 and its activation in lung adenocarcinoma in vitro, since lung adenocarcinomas from premenopausal women have shown high levels of CXCR4, and this expression has been associated with worse prognosis and poor survival. METHODS: The effect of 17-ß-estradiol (E2) (0.03 nM-10 nM) on CXCR4 expression was analyzed in lung adenocarcinoma cell lines (SK-LU-1, H1435, H23, A549) by immunofluorescence after 24 and 72-h poststimulation. Tamoxifen treatment was applied to corroborate the estrogenic effect. The wound-healing assay was performed to investigate whether E2 treatment increased CXCR4/CXL12 pathway activity. A549 and SK-LU-1 cells were stimulated with E2, CXCL12, and CXCL12 combined with E2. Tamoxifen and AMD3100 were applied to corroborate estrogen and chemokine pathway activation. RESULTS: Estradiol stimulated significantly CXCR4 overexpression in all the cell lines analyzed in a dose- and a time-dependent manner. Tamoxifen treatment inhibited the CXCR4 overexpression observed in estrogen-treated groups, demonstrating that estrogen strongly influences CXCR4 expression in lung adenocarcinoma cells. Cells treated with E2, CXCL12 and E2 combined with CXCL12 exhibited significant cell migration, which was suppressed when tamoxifen and AMD3100 were present. CONCLUSION: Overexpression of CXCR4 induced by estrogen and the activity of CXCL12/CXCR4 pathway could be a new mechanism by which this hormone supports tumor progression and metastasis. These findings may partly explain the worse prognosis observed in premenopausal women and suggest considering the role of estrogen in lung cancer for the design of more specific treatment schemes.

Sex-based differences in lymphocyte proliferation in the spleen after vanadium inhalation.

Vanadium (V) is a transition metal often adhered to particulate matter and released into the atmosphere as vanadium pentoxide (V2O5) by the burning of fossil fuels. This air pollutant causes adverse effects in the immune system. Lymphocytosis and splenomegaly have been reported with increased white pulp in mice after V inhalation. The effect of V on the immune system as related to sex has been poorly investigated. This study sought to determine if V inhalation (a) produced lymphoproliferation that could explain the changes previously observed in the spleen and in peripheral blood lymphocyte counts and (b) whether any observed effects differed due to gender. Immunohistochemical analyses of Ki-67, a specific proliferation marker, was made in the spleens of CD-1 male and female mice exposed for 1 h, twice a week, over a 12-week period to V2O5 (at 1.4 mg V2O5/m(3)) by whole-body inhalation; similar analyses were performed on spleens of control mice exposed to vehicle (filtered air). The results showed that in male mice there was a significant increase in percentage of Ki-67 immunopositive lymphocytes starting from the second week and until the end of the exposure. The Ki-67 signal was cytoplasmic and nuclear in the exposed males, while in controls the signal was only nuclear. In female mice, V inhalation singificantly increased the percentage of proliferating lymphocytes only after 1 week of exposure. Ki-67 signal was observed only in the nucleus of lymphocytes from the control and exposed females. The results here help to explain the splenomegaly and lymphocytosis observed previously in male mice and support the lymphoproliferative effect induced by V. Lastly, the finding that there was a sex difference in the effect of vanadium on lymphocyte proliferation suggests a role for sex hormones in potential protection against V immunotoxicity; however, further studies are needed to support this hypothesis.

Estrógenos y su influencia en el cáncer pulmonar / The influence of estrogens in lung cancer

Resumen Actualmente, el cáncer pulmonar es un problema de salud importante a nivel mundial porque presenta una alta incidencia y mortalidad tanto en hombres como en mujeres. Su forma más común es el adenocarcinoma (ADC), que es una entidad patológica interesante ya que de todas las formas de cáncer pulmonar, es la que se asocia menos con el tabaquismo y un porcentaje importante de pacientes con adenocarcinoma son no fumadores. De modo que otros factores como la exposición al humo de leña, a los contaminantes del aire, la historia familiar de cáncer, entre otros, son importantes para el desarrollo del ADC pulmonar. Actualmente el ADC pulmonar es la principal forma de cáncer pulmonar en las mujeres y se ha reportado que las mujeres premenopáusicas presentan peor pronóstico y los tumores son más agresivos cuando se comparan con los hombres y las mujeres posmenopáusicas. Estos datos han sugerido el papel de los estrógenos en el cáncer pulmonar, principalmente en el ADC. Aunque existe vasta evidencia epidemiológica que demuestra esta relación, hay controversia en cuanto al papel de los estrógenos en esta patología. De igual manera no hay una opinión generalizada sobre los mecanismos por los cuales los estrógenos podrían favorecer la carcinogénesis. Sin embargo, cada vez es más clara la importancia de éstas hormonas en la carcinogénesis pulmonar. En esta revisión se muestran estos datos y se discute la relevancia de los estrógenos en el cáncer pulmonar, una patología cuya dependencia hormonal es cada vez más clara.

Abstract Lung cancer is currently a worldwide health issue because of the mortality and high incidence of this pathology in both men and women. The most common form of lung cancer is adenocarcinoma (ADC); It is an interesting disease entity because among every type of lung cancer it has the lower association with smoking and a significant percentage of patients with adenocarcinoma are not smokers. Hence other factors such as exposure to wood-smoke, air pollutants, family history of cancer, among others, are important in the development of lung ADC. Nowadays, lung ADC is the main form of lung cancer in women and reports show that premenopausal women have the worse prognosis and have more aggressive tumors compared to men and postmenopausal women. These data suggests that estrogens have a particular role in lung cancer physiopathology mainly in ADC. Although there is sufficient epidemiological evidence that indicates a relationship between sexual hormones and lung cancer, the role of estrogens in this pathology is still controversial. Furthermore there is no general consent regarding the known mechanisms by which these hormones could promote carcinogenesis and because the scarce information about the implication of these hormones in lung carcinogenesis more studies are needed. In this review we discuss the role and relevance of estrogens in lung cancer, a pathology whose hormonal dependency is becoming clearer.

Estrogen receptor beta and CXCR4/CXCL12 expression: differences by sex and hormonal status in lung adenocarcinoma.

BACKGROUND AND AIMS: Studies have reported differences in lung cancer behavior between sex and hormonal status that suggest a role of estrogens and estrogen receptor beta (ERß) in lung carcinogenesis. In some types of hormone-dependent cancer, estrogens may regulate CXCL12/CXCR4 expression through ERß signaling. High expression of CXCL12/CXCR4 is associated with poor prognosis in lung cancer because it promotes tumor growth and metastasis. Therefore, in this study we investigated whether lung adenocarcinoma tissues from pre- and postmenopausal women and from men exhibit different ERß, CXCR4/CXCL12 expression and whether this expression is associated with clinicopathological features. METHODS: Sixty primary tumor samples of lung adenocarcinoma from pre- and postmenopausal women and from men were collected for this study. Thirty samples of healthy lung tissue adjacent to the tumor site were used as controls. ERß and CXCL12/CXCR4 expression was analyzed by immunohistochemistry. Expression of these proteins was measured by digital image software and compared between sex and hormonal status. RESULTS: Lung adenocarcinomas overexpressed ERß, CXCR4 and CXCL12 compared to normal lung. Moreover, lung adenocarcinomas from premenopausal women exhibited higher signals for ERß, CXCL12 and CXCR4 compared to postmenopausal women and to men, who showed lower signals for these proteins. A multivariate analysis revealed a strong association between the immunoreactivity level of ERß, CXCL12/CXCR4 and both sex and hormonal status, but not with tumor stage and smoking. CONCLUSION: These results demonstrated that ERß and CXCL12/CXCR4 expression in lung adenocarcinoma depends on sex and hormonal status, which may partly explain the sex and hormonal differences in lung cancer behavior.

Ultrastructural megakaryocyte modifications after vanadium inhalation in spleen and bone marrow.

Previous reports from our laboratory informed in mice an increase in platelets in blood, and megakaryocytes in spleen and bone marrow after vanadium inhalation. This element has become important in recent years because of its increased presence as an air pollutant. With this precedent, we evaluate the ultrastructural modifications in MKs from the spleen and bone marrow in our mouse experimental model. Mice inhaled 0.02 M V(2)O(5) 1 h twice a week for 12 weeks. Tissues were processed for transmission electron microscopy. Results indicate an increase in the size and cytoplasmic granular content, as well as nuclear changes in MKs of exposed mice, changes which correlate with the time of exposure. Modifications in MKs described here suggest that inhaled vanadium induce megakaryocytic maturation, a raise in its granules content and demarcation membrane systems, which may lead to a rise in circulating platelet production and an increased risk for thromboembolic events.

Spleen and bone marrow megakaryocytes as targets for inhaled vanadium.

An increased incidence in ischemic and thromboembolic events in the population of cities with rising air suspended particle pollution has suggested the interaction of some of the components of these particles in the coagulation system. A previous report from our laboratory identified thrombocytosis as a consequence of the subacute and chronic inhalation of vanadium. With this preceding information we decided to evaluate the effects of this element in the spleen and bone marrow in a mouse experimental model. CD-1 male mice inhaled V2O5 0.02 M for one hour twice a week for twelve weeks. The spleen and bone marrow were processed for light microscopy. The increase in quantity and size of megakaryocytes (MKs) in the exposed group in both organs was striking. Also, modifications in the cytoplasm, granule content and nuclear ultrastructure were evident. Our results indicate the influence of vanadium on megakaryopoyesis, an effect which could be the onset of the thrombocytosis previously reported by our group. The modifications in MKs described here suggest that inhaled vanadium could induce megakaryocytic proliferation, which may result in increased production of platelets and increased risk for thromboembolic events.