FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale

Abstract

BackgroundTreatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.Materials and MethodsPrimary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.ResultsPD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.ConclusionHigh tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

Anaplastic Thyroid Carcinoma: An Update

“…Among these inhibitory immune checkpoint molecules, PD-L1 expression has been identified in 70% of ATC samples in the pre-clinical study by Schürch et al [ 49 ] and in the phase I study of spartalizumab [ 10 ]. PD-L1 expression based on the proportion of stained tumor cells according to Tumor Proportion Score (TPS) has been found at ≥5% in 73% of 93 samples in a recent multicenter study from Germany [ 51 ]. In the tumor microenvironment, PD-L1 can be upregulated in both tumor cells and immune-microenvironment cells, such as TAMs in ATC samples [ 52 , 53 ].…”

“…PD-L1 has been suggested as a predictive biomarker of response to ICI in several cancers although its robustness has been questioned. As described above, PD-L1 is often expressed on ATC tumor cells, suggesting new treatment opportunities for ATC with immunotherapy [ 10 , 51 ]. Indeed, spartalizumab, an anti-PD-1 antibody, has been studied in ATC [ 10 ].…”

Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid Cancer: A Case Report

“…A prospective multicentric phase II trial did not confirm the encouraging results of a Japanese phase II study of lenvatinib in ATC patients and was interrupted due to the absence of efficacy [ 18 , 19 ]. Recent studies suggested that one start the treatment with lenvatinib alone and add pembrolizumab upon disease progression [ 4 , 20 , 21 , 22 ]. However, some TKIs induce modifications of the tumor environment that inhibit the anti-tumor immune response, thus contributing to immune resistance and progression of disease [ 23 ].…”

Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications

“…RNAScope is a custom RNA in-situ hybridization solution from Advanced Cell Diagnostics, USA. Version 2.0 of the kit was utilized for our experiments following the manufacturer’s instructions as described before ( 40 ). In short, the FFPE tissue sections of ~2µm thickness were mounted on SuperFrost glass slides (Langenbrinck, Germany), deparaffinized in xylene then washed with 100% ethanol followed by endogenous enzyme blocking in hydrogen peroxide solution (ref.…”