Abstract 2737: Does androgen attenuation of PD-L1 expression in thyroid cancer modulate disease incidence
Authors: Timmy J. O'Connell, Anvita Gupta, Melanie Jones, Tali Lando, Deya Jourdy, Edward Shin, Augustine Moscatello, Raj Tiwari, Jan Geliebter
Journal: Cancer Research (2018)

Abstract Thyroid cancer (ThCa) is the most rapidly increasing cancer in the US with 56,870 new cases expected in 2017. Interestingly, there is a disparity in incidence between females and males, with women developing ThCa three times more often than men. Immune elimination of nascent tumor cells may explain the difference in disease incidence between sexes. To address this hypothesis, the effect of androgen on immune checkpoint molecule expression in an androgen responsive-thyroid cancer cell line was examined. The undifferentiated ThCa cell line, 8505C, was transfected with androgen receptor (AR) yielding 84E7, a clone that constitutively expresses AR. RNASeq was performed on 8505C and 84E7, treated without and with the AR ligand, 5α-dihydrotestosterone (DHT). PD-L1 was the sole immune checkpoint molecule that exhibited a significant expression change with a 72% reduction in mRNA content. Additional studies provided evidence of qualitative (immunofluorescence) and quantitative (flow cytometry, western blotting) DHT-mediated decreases in PD-L1 expression, with the PD-L1 decreases being both time- and dose-dependent. To further confirm that the effect was specific to AR and PD-L1, we pre-treated 84E7 with flutamide, a selective AR antagonist, to pharmacologically inhibit DHT-mediated AR signaling. This resulted in a dose-dependent and &amp;gt;90% restoration of cell surface PD-L1 expression, evidencing a definitive link between AR activation and PD-L1 signaling. Preliminary investigation into the mechanistic link between AR and PD-L1 shows that NFkB signaling is the likely intermediary. AR activation increases IkBα expression thereby preventing NFkB translocation into the nucleus, resulting in decreased PD-L1 transcription. Furthermore, in human tissue samples from TCGA (n=55), we found female thyroid tissue is significantly enriched with PD-L1 as compared to male thyroid tissue (p=0.0073). Finally, an inverse relationship exists in which AR expression is decreased and PD-L1 expression is increased in human thyroid tumor tissue samples as compared to normal thyroid tissue samples in both TCGA (n=55, p&amp;lt;0.005) and NYMC (n=56, p&amp;lt;0.005) RNAseq datasets. These results are significant in that PD-L1 is expressed by tumor cells as a strategy for evading the immune response allowing for continued tumor growth and metastases. In the thyroid, the presence of androgen-activated AR could lead to an environment that is more favorable for immune system activation and may help eliminate nascent ThCa cells. Thus, men experience a decreased incidence of ThCa due to an immunologically enhanced anti-tumor microenvironment. Alternatively, higher expression levels of PD-L1 observed in female thyroid cancer patients help explain the increased incidence of ThCa and may indicate an opportunity for sex-based therapeutics. Citation Format: Timmy J. O'Connell, Anvita Gupta, Melanie Jones, Tali Lando, Deya Jourdy, Edward Shin, Augustine Moscatello, Raj Tiwari, Jan Geliebter. Does androgen attenuation of PD-L1 expression in thyroid cancer modulate disease incidence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2737.