Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer

Area of Science:

• Endocrinology
• Cancer Biology
• Immunology

Background:

• Thyroid cancer is the most common endocrine malignancy in the US, with women disproportionately affected.
• The reasons for the gender disparity in thyroid cancer incidence remain unclear.
• Immune checkpoint molecules, such as PD-L1, play a critical role in cancer immune evasion.

Purpose of the Study:

• To investigate the role of androgen receptor (AR) signaling in regulating PD-L1 expression in papillary thyroid cancer (PTC).
• To explore the potential impact of sex hormones on the tumor immune microenvironment and immunotherapy efficacy.

Main Methods:

• RNA-sequencing was used to profile the immune landscape of PTC.
• Androgen-responsive thyroid cancer cell lines were treated with dihydrotestosterone (DHT) and flutamide (an AR antagonist).
• Cell surface PD-L1 expression was measured using flow cytometry; AR binding sites and NF-kB signaling were investigated.

Main Results:

• A significant inverse correlation was found between AR levels and PD-L1 expression in PTC.
• DHT treatment dose- and time-dependently reduced PD-L1 expression on thyroid cancer cells.
• AR antagonism with flutamide restored PD-L1 expression, confirming AR-dependent regulation.
• AR activation was shown to inhibit NF-kB signaling, reducing PD-L1 promoter activity.

Conclusions:

• Androgen receptor signaling negatively regulates PD-L1 expression in thyroid cancer cells in vitro.
• This study elucidates a novel mechanism of immune checkpoint regulation by sex hormones.
• Findings suggest potential therapeutic strategies targeting the AR-PD-L1 axis for thyroid cancer immunotherapy.