Deciphering the immune landscape of parathyroid carcinoma: implications for immunotherapeutic responsiveness

Parathyroid carcinoma is a rare endocrine malignancy with limited therapeutic options. Immune checkpoint blockade targeting the PD-1/PD-L1 axis has transformed the management of several solid tumors; however, its role in parathyroid carcinoma remains largely unexplored. Given that the response to immunotherapy is influenced not only by PD-L1 expression but also by the tumor immune microenvironment (TIME), characterization of the immune landscape in parathyroid carcinoma may provide insights into its potential therapeutic vulnerability.

To evaluate PD-L1 expression and comprehensively characterize the tumor immune microenvironment in parathyroid carcinoma, enabling identification of features predictive of immunotherapeutic responsiveness.

Using immunohistochemistry and multiplex immunofluorescence, this ambispective study investigated parathyroid carcinoma, parathyroid adenoma, and normal parathyroid tissues for PD-L1 expression (clone SP263, Ventana), infiltrating immune cells, namely cytotoxic T lymphocytes (CTLs; CD3⁺CD8⁺), regulatory T cells (Tregs; CD4⁺CD25⁺FOXP3⁺), and monocytic myeloid-derived suppressor cells (MDSCs; CD11b⁺CD14⁺). Immune cell densities were quantified per mm², and the TIME was categorized into four types based on PD-L1 expression and the presence of CTLs: Type I (PD-L1⁺/CTL-rich, adaptive immune resistance), Type II (PD-L1⁻/CTL-poor, immune ignorance), Type III (PD-L1⁺/CTL-poor, intrinsic induction), and Type IV (PD-L1⁻/CTL-rich, immune tolerance).

While 30% of adenomas showed patchy PD-L1 positivity (Tumor proportion score, TPS 3-6%), all carcinomas and normal parathyroid tissues were PD-L1-negative (TPS < 1%). Among the immune cells, CTLs and MDSCs were more abundant in the TIME of parathyroid carcinomas than in adenomas and normal tissues. Tregs were rare or absent. Parathyroid carcinomas demonstrated immune-tolerant (Type IV) or immunologically ignorant (Type II) microenvironmental profiles.

Parathyroid carcinomas predominantly exhibit a PD-L1-independent immune-tolerant microenvironment, rich in CTLs and MDSCs. The results predict a limited benefit from single-agent PD-1/PD-L1 blockade and the need for myeloid-targeting and immune-priming multimodal strategies.