Programmed Death-1+ T Cells and Regulatory T Cells Are Enriched in Tumor-Involved Lymph Nodes and Associated with Aggressive Features in Papillary Thyroid Cancer

Abstract

Context: Recurrent metastatic lymph node (LN) disease is common in patients with papillary thyroid cancer (PTC). Novel prognostic markers may be helpful in guiding a therapeutic approach. Our previous studies revealed that immune suppression is evident in PTC and associated with more severe disease. Objective: To characterize the immune response to metastatic PTC, we assessed CD4⁺ T cell polarization in LN. In addition, we investigated the role of programmed death-1 (PD-1) and T cell exhaustion. Design: Uninvolved (UILN) and tumor-involved lymph nodes (TILN) were sampled ex vivo by fine-needle biopsy. T cell subsets were identified by flow cytometry. In parallel, archived TILN specimens were characterized by immunofluorescence. Setting: The study was conducted at the University of Colorado Hospital. Patients: Data were collected on 94 LN from 19 patients with PTC undergoing neck dissection. Main Outcome: T cell subset frequencies were compared in UILN and TILN and assessed for correlation with recurrent disease and extranodal invasion. Results: Regulatory CD4⁺ T cells (Treg) were enriched in TILN compared with UILN and further elevated in TILN from patients with recurrent disease. PD-1⁺ T cells were present at high frequency in TILN and markedly enriched in TILN that showed evidence of extranodal invasion. In TILN, Treg frequency correlated with PD-1⁺ T cell frequencies. Although PD-1⁺ T cells produced interferon-γ, they failed to fully down-regulate CD27 and were not actively proliferating. Conclusions: Increased Treg and PD-1⁺ T cell frequencies in LN may be indicative of aggressive recurrent PTC. Future prospective studies are necessary to determine the prognostic and therapeutic value of these findings in PTC.