title: Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer.
abstract: Five to 10% of patients with differentiated thyroid cancers (DTC) develop invasive and/or distant metastatic disease that is marginally improved with standard therapies. Prognosis is poor for patients with anaplastic thyroid cancer, with a median survival of 3-5 months. We suggest that a paradigm shift is necessary in the treatment of advanced cases.
  
  
  
  We hypothesized that a T-cell response is generated in advanced thyroid cancer and may be a viable therapeutic target.
  
  
  
  Primary DTCs were analyzed by quantitative RT-PCR (n = 92) for expression of CD3, CD8, forkhead box (Fox)-P3, programmed death (PD)-1, PD-1 ligand-1, and PD-1 ligand-2 and biopsied for cellular analysis by flow cytometry (n = 11). Advanced pT4 cases (n = 22) and metastases (n = 5) were analyzed by immunohistochemistry.
  
  
  
  The study was conducted at the University of Colorado Hospital.
  
  
  
  Thyroid cancer patients undergoing thyroidectomy or completion surgery for advanced disease between 2002 and 2013 participated in the study.
  
  
  
  There were no interventions.
  
  
  
  Immune markers were analyzed for association with disease severity.
  
  
  
  Immune markers were commonly expressed at the RNA level. PD-L1 was higher (P = .0443) in patients with nodal metastases. FoxP3(+) (P < .0001), PD-1(+)CD8(+) (P = .0058), and PD-1(+)CD4(+) (P = .0104) T cells were enriched in DTC biopsies. CD8(+) and FoxP3(+) T cells were detected by immunohistochemistry in all pT4 tumors and a subset of metastases. PD-1(+) lymphocytes were found in 50% of DTCs. PD-L1 was expressed by tumor and associated leukocytes in 13 of 22 cases, and expression was more diffuse in anaplastic thyroid cancer (P = .0373). BRAF(V600E) mutation was associated with higher frequencies of tumor-associated lymphocytes (P = .0095) but not PD-L1 expression.
  
  
  
  PD-1 checkpoint blockades may have therapeutic efficacy in patients with aggressive forms of thyroid cancer.
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Jill J
authors.initials: JJ
authors.lastname: Bastman
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Hilary S
authors.initials: HS
authors.lastname: Serracino
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Koenig
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Valerica
authors.initials: V
authors.lastname: Mateescu
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Sams
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Kurtis D
authors.initials: KD
authors.lastname: Davies
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Raeburn
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Robert C
authors.initials: RC
authors.lastname: McIntyre
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Haugen
authors.affiliation: Department of Medicine (J.J.B., B.R.H., J.D.F.), Division of Endocrinology, Metabolism, and Diabetes, Departments of Pathology (H.S.S., V.M., S.B.S., K.D.D., B.R.H.) and Surgery (Y.Z., M.R.K., R.C.M., C.D.R.), and University of Colorado Cancer Center (B.R.H., J.D.F.), University of Colorado Denver, Aurora, Colorado 80045.
authors.forename: Jena D
authors.initials: JD
authors.lastname: French
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics; D065646:Thyroid Carcinoma, Anaplastic / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor