Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile

Our plain-English summary of Expression patterns of estrogen and androgen receptors in NSCLC patients according to the PD-L1 profile, by V. Rodriguez-Lara, G. Cortés-Ramírez, I.A. Angeles-Torres, et al (Frontiers in Immunology, 2025).

The study

• Authors: V. Rodriguez-Lara, G. Cortés-Ramírez, I.A. Angeles-Torres, J. Rodriguez-Cid, S.M.L. Pedraza-Reyes, M.R. Avila-Costa, J.L. Ordoñez-Librado, M. Cerbón
• Journal: Frontiers in Immunology
• Published: 2025;16:1602579
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Lung cancer is the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the most common type. Immunotherapy targeting programmed death ligand-1 (PD-L1) blockade has significantly improved survival, but differences in responses by sex have been reported, suggesting a possible role of sex hormones. Estrogens and androgens, through their receptors support lung carcinogenesis, but their role in immune evasion via the PD-1/PD-L1 pathway remains poorly understood.

Materials And Methods: We analyzed by immunohistochemistry the expression patterns of estrogen receptors (ERα and ERβ) and androgen receptor (AR) in 95 PD-L1-positive (PD-L1+) and 72 PD-L1 negative (PD-L1-) NSCLC patients by sex and hormonal status. We also investigated associations between hormonal receptors, PD-L1 profile, PD-L1 tumor proportion score (TPS), and clinical features (cancer stage according to the TNM stage of cancer, smoking history, wood smoke exposure, and asbestos exposure).

Results: ERβ was the predominant form of estrogen receptor in PD-L1- patients, while ERα expression was significantly higher in PD-L1+ patients and strongly associated with the PD-L1+ profile, regardless of sex or hormonal status. AR expression was low across all groups and showed no association with PD-L1. Among PD-L1+ patients, ERα expression levels were highest in premenopausal women, followed by men and postmenopausal women. ERα levels in the PD-L1+ group, were not associated with PD-L1 TPS or with clinical features.

Conclusion: The estrogen pathway, particularly via ERα, plays a key role in PD-L1 expression and may contribute to tumor immune evasion. Antiestrogen therapy could represent a promising strategy to enhance immunotherapy efficacy in patients expressing ERs.

Copyright © 2025 Rodriguez-Lara, Cortés-Ramírez, Angeles-Torres, Rodriguez-Cid, Pedraza-Reyes, Avila-Costa, Ordoñez-Librado and Cerbón.

In plain English

This retrospective study examined lung tumor biopsies, taken before treatment, from patients with non-small cell lung cancer (NSCLC) diagnosed in 2018 to 2024 at a respiratory hospital in Mexico City. The authors compared 95 tumors positive for PD-L1, a protein targeted by immunotherapy, with 72 PD-L1-negative tumors. They stained the tumors for estrogen receptors alpha and beta and for the androgen receptor. In PD-L1-negative tumors, estrogen receptor beta was the most common. In PD-L1-positive tumors, receptor alpha was most common (100% of premenopausal women, 77% of postmenopausal women, 71% of men), and patients expressing it had an adjusted odds ratio of 5.01 for being PD-L1-positive. Among PD-L1-positive patients, receptor alpha levels were significantly higher in premenopausal women than in the other groups. The androgen receptor was uncommon and was not associated with PD-L1. Asbestos exposure, taken from clinical records, was one of the clinical features examined. It showed no statistically significant association with receptor alpha levels in PD-L1-positive patients. The authors concluded that estrogen, mainly through receptor alpha, plays a key role in PD-L1 expression and that antiestrogen therapy could be a strategy to enhance immunotherapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective study of stored tumor biopsy tissue, using immunohistochemistry (tissue staining) to detect hormone receptors
• Who was studied: 167 patients with non-small cell lung cancer at the National Institute of Respiratory Disease (INER), Mexico City, diagnosed between 2018 and 2024 and untreated at the time of biopsy. 95 were PD-L1-positive (17 premenopausal women, 36 postmenopausal women, 42 men) and 72 were PD-L1-negative (21 premenopausal women, 29 postmenopausal women, 22 men). Women who had undergone oophorectomy or received hormone replacement therapy were excluded.
• Exposure: The main factors studied were tumor expression of estrogen receptor alpha, estrogen receptor beta and androgen receptor, compared by PD-L1 status, sex and menopausal status. Asbestos exposure, smoking and wood smoke exposure were recorded from clinical records as clinical features. No fiber type, job or dose of asbestos exposure is described.
• Main results:
  • In PD-L1-negative patients, estrogen receptor beta was the predominant estrogen receptor: 80.9% of premenopausal women, 60.7% of postmenopausal women and 66% of men.
  • In PD-L1-positive patients, estrogen receptor alpha was the main estrogen receptor: 100% of premenopausal women, 77% of postmenopausal women and 71% of men.
  • The proportion of patients with estrogen receptor alpha was higher in the PD-L1-positive group than in the PD-L1-negative group (p less than 0.0001). In a model adjusted for factors such as sex and hormonal status, patients expressing receptor alpha had an odds ratio of 5.01 for being PD-L1-positive. No confidence interval is printed.
  • Estrogen receptor beta (p=0.8194) and the androgen receptor (p=0.399) were not significantly associated with PD-L1 status.
  • Co-expression of estrogen receptors alpha and beta was significantly higher in PD-L1-positive patients than in PD-L1-negative patients (p less than 0.0001).
  • Among PD-L1-positive patients, estrogen receptor alpha levels differed by group. The difference was significant only for premenopausal women compared with postmenopausal women and men.
  • Among PD-L1-positive patients, estrogen receptor alpha expression was not significantly associated with the PD-L1 tumor proportion score.
  • Among PD-L1-positive patients, asbestos exposure was not significantly associated with estrogen receptor alpha levels in the mixed-effects model (b = -0.54, SE = 25.61, t = -0.021). Smoking, wood smoke exposure and TNM stage were not significantly associated either.
  • Asbestos exposure in the PD-L1-negative group, as read from a flattened table: 2 premenopausal women (9.5%), 2 postmenopausal women (6.8%) and 2 men (9%).
  • Asbestos exposure in the PD-L1-positive group, as read from a flattened table: 1 premenopausal woman (5.8%), 3 postmenopausal women (8.3%) and 1 man (2.3%).
• The authors' conclusion: The authors concluded that estrogens, mainly through estrogen receptor alpha, play a significant role in regulating PD-L1 expression in lung cancer in both men and women, and that the androgen pathway was not associated with PD-L1 expression. They suggested that antiestrogen therapy combined with PD-L1 inhibitors could be explored, particularly in premenopausal women, and called for further studies.
• Limitations the authors state:
  • The authors note that sex differences in PD-L1 expression and immunotherapy response might be explained by factors other than sex hormones, such as smoking habits and KRAS mutation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: PD-L1, Lung Cancer, Non-Small Cell Lung Cancer, Immunotherapy, Carcinogenesis, PD-1/PD-L1, Immunohistochemistry, Asbestos Exposure.

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