Macrophage abundance in oncocytic thyroid cancer is associated with PD-L1 expression

Oncocytic thyroid cancer (OTC) accounts for 3-5% of thyroid cancers. Previously classified as a subtype of follicular thyroid cancer (FTC), OTC has been redefined by the World Health Organization due to its distinct histopathological and molecular features. OTC demonstrates a more aggressive clinical course than other differentiated thyroid cancers, with higher rates of distant metastases and is often refractory to radioactive iodine therapy (RAI). This study investigates the transcriptional profiles and immune populations of OTC and FTC to identify key differences in gene signatures and immune cell populations.

We conducted a comparative analysis of the transcriptional profiles of OTC (n = 12), FTC (n = 8), and non-neoplastic thyroid tissues (n = 9) using targeted RNA sequencing and assessed immune composition through multiplexed immunohistochemistry. PD-L1 and CD68 were evaluated by immunostaining consecutive sections.

Functional enrichment analysis of differentially expressed genes between OTC and non-neoplastic thyroids revealed upregulation of metabolic pathway genes and downregulation of genes from the cytokine-cytokine receptor pathway. Compared to FTC, OTC cases have decreased expression of thyroid differentiation genes. CD274/PD-L1 was among the top upregulated genes in OTC vs FTC. PD-L1 protein expression in OTC was tumor cell-derived and correlated with CD68+ macrophage presence, particularly in widely invasive cases.

The heightened metabolic activity and reduced differentiation of OTC revealed by our transcriptional studies correlate with clinical features such as FDG-PET avidity and diminished RAI response. Marked PD-L1 upregulation in widely invasive OTC suggests immune checkpoint inhibition as a potential therapeutic strategy. Larger, independent studies will be critical to validate these findings.