HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line
- PDF / 8,482,668 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 76 Downloads / 189 Views
ORIGINAL ARTICLE
HDAC Inhibition Induces PD-L1 Expression in a Novel Anaplastic Thyroid Cancer Cell Line Luca Hegedűs 1 & Dominika Rittler 2 & Tamás Garay 2,3 & Paul Stockhammer 1,4 & Ildikó Kovács 5 & Balázs Döme 4,5,6 & Sarah Theurer 7 & Thomas Hager 7 & Thomas Herold 7 & Stavros Kalbourtzis 7 & Agnes Bankfalvi 7 & Kurt W. Schmid 7 & Dagmar Führer 8 & Clemens Aigner 1 & Balázs Hegedűs 1,2 Received: 6 April 2020 / Accepted: 26 May 2020 # The Author(s) 2020
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 paclitaxelcisplatin 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. Keywords Anaplastic thyroid cancer . BRAF mutation . TERT promoter mutation . HDAC inhibition . Pleural effusion
Background 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]. In rare occasions, a papillary thyroid carcinoma can also transform to an anaplastic carcinoma as it was demonstrated in several case studies [4, 5]. ATC has a heterogeneous mutational background. 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 also present in around 40% of the tumors [7, 8] and shows association with both the presence of BRAF mutation and advanced
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12253-020-00834-y) contains supplementary material, which is available to authorized users. * Balázs Hegedűs [email protected] 1
2
3
4
Department of Thoracic Surgery, Medical University
Data Loading...