title: 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: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  The study was conducted at the University of Colorado Hospital.
  
  
  METHODS
  Data were collected on 94 LN from 19 patients with PTC undergoing neck dissection.
  
  
  RESULTS
  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.
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora, Colorado 80045, USA. jena.french@ucdenver.edu
authors.forename: Jena D
authors.initials: JD
authors.lastname: French
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Kotnis
authors.forename: Sherif
authors.initials: S
authors.lastname: Said
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Raeburn
authors.forename: Robert C
authors.initials: RC
authors.lastname: McIntyre
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Klopper
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Haugen
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D044963:Biopsy, Fine-Needle; D002291:Carcinoma, Papillary / Q000378:metabolism* / Q000401:mortality / Q000556:secondary / Q000601:surgery; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008213:Lymphocyte Activation / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000601:surgery; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000601:surgery
chemical_list: D014408:Biomarkers, Tumor; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor