HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line

Luca Hegedűs,Ildikó Kovács,Agnes Bankfalvi,Dominika Rittler,Thomas Herold,Kurt W Schmid,Stavros Kalbourtzis,Paul Stockhammer,Balázs Hegedűs,Clemens Aigner,Dagmar Führer,Tamás Garay,Sarah Theurer,Thomas Hager,Balázs Döme

doi:10.1007/s12253-020-00834-y

Abstract

While papillary thyroid cancer (PTC) has largely favorable prognosis, anaplastic thyroid cancer (ATC) is a rare but extremely aggressive malignancy with grim clinical outcome. Even though new therapeutic options are emerging for ATC, additional preclinical models and novel combinations are needed for specific subsets of patients. We established a novel cell line (PF49) from the malignant pleural effusion of a 68-year-old male patient with ATC that rapidly transformed from a BRAF and TERT promoter mutant PTC. PF49 cells demonstrated a robust migratory activity in vitro and strong invasive capacity in vivo in a pleural carcinosis model. Combined BRAF and MEK inhibition decreased the proliferation and migration of PF49 cells, however could not induce cell death. Importantly, HDAC inhibitor treatment with SAHA or valproic acid induced cell cycle arrest and strongly increased PD-L1 expression of the tumor cells. Induction of PD-L1 expression was also present when paclitaxel-cisplatin chemotherapeutic treatment was combined with HDAC inhibitor treatment. Increased PD-L1 expression after HDAC inhibition was recapitulated in an international ATC cell model. Our data suggest that HDAC inhibition alone or in combination with standard chemotherapy may potentiate anaplastic thyroid cancer cells for immunotherapy.

Highlights

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease that represents 1–2% percent of thyroid cancer cases but it is responsible for around 30% of thyroid cancer related death and the 5-year relative survival rate is around 10% [1, 2]
Cell cycle analysis showed that both valproic acid and Suberoylanilide hyroxamic acid (SAHA) treatment induced cell cycle arrest in the G2M phase in more than 50% of the cells, and in the case of SAHA this effect was already observed at a lower treatment concentration (1 μM) (Fig. 5b)
While patients with differentiated thyroid cancers have a good prognosis with long term survival when receiving the standard therapy, anaplastic thyroid cancer has a really poor outcome due to its high metastatic capacity and poor response to both radioiodine and chemotherapeutic treatments

Summary

Introduction

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease that represents 1–2% percent of thyroid cancer cases but it is responsible for around 30% of thyroid cancer related death and the 5-year relative survival rate is around 10% [1, 2]. It mostly develops from follicular derived differentiated thyroid cancers or directly from normal follicular thyroid cells [3]. Mutation in the BRAF gene was described in 25% of the cases, while the prevalence of RAS gene mutations is around 10–25% [6]. TERT promoter mutation is present in around 40% of the tumors [7, 8] and shows association with both the presence of BRAF mutation and advanced

Methods

Results

Conclusion