RNA Therapeutics Institute; Medical Scientist Training Program, Graduate School of Biomedical Sciences
Cancer Biology | Cell Biology | Hormones, Hormone Substitutes, and Hormone Antagonists | Immunopathology
Thyroid cancer is the most prevalent endocrine malignancy in the United States with greater than 53,000 new cases in 2020. There is a significant gender disparity in disease incidence as well, with women developing thyroid cancer three times more often than men; however, the underlying cause of this disparity is poorly understood. Using RNA-sequencing, we profiled the immune landscape of papillary thyroid cancer (PTC) and identified a significant inverse correlation between androgen receptor (AR) levels and the immune checkpoint molecule PD-L1. The expression of PD-L1 was then measured in an androgen responsive-thyroid cancer cell line. Dihydrotestosterone (DHT) treatment resulted in significant reduction in surface PD-L1 expression in a time and dose-dependent manner. To determine if androgen-mediated PD-L1 downregulation was AR-dependent, we treated cells with flutamide, a selective AR antagonist, and prior to DHT treatment to pharmacologically inhibit AR-induced signaling. This resulted in a > 90% restoration of cell surface PD-L1 expression, suggesting a potential role for AR activity in PD-L1 regulation. Investigation into the AR binding sites showed AR activation impacts NF-kB signaling by increasing IkBalpha and by possibly preventing NF-kB translocation into the nucleus, reducing PD-L1 promoter activation. This study provides evidence of sex-hormone mediated regulation of immune checkpoint molecules in vitro with potential ramification for immunotherapies.
PD-L1 pathway, androgen receptor, gender disparity, immune surveillance, thyroid cancer
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Copyright © 2021 O’Connell, Dadafarin, Jones, Rodríguez, Gupta, Shin, Moscatello, Iacob, Islam, Tiwari and Geliebter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
DOI of Published Version
O'Connell TJ, Dadafarin S, Jones M, Rodríguez T, Gupta A, Shin E, Moscatello A, Iacob C, Islam H, Tiwari RK, Geliebter J. Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer. Front Cell Dev Biol. 2021 Aug 6;9:663130. doi: 10.3389/fcell.2021.663130. PMID: 34422798; PMCID: PMC8377372. Link to article on publisher's site
Frontiers in cell and developmental biology
O'Connell TJ, Dadafarin S, Jones M, Rodríguez T, Gupta A, Shin E, Moscatello A, Iacob C, Islam H, Tiwari RK, Geliebter J. (2021). Androgen Activity Is Associated With PD-L1 Downregulation in Thyroid Cancer. Open Access Publications by UMass Chan Authors. https://doi.org/10.3389/fcell.2021.663130. Retrieved from https://escholarship.umassmed.edu/oapubs/4886
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