title: CD44+ Cells in Head and Neck Squamous Cell Carcinoma Suppress T-Cell-Mediated Immunity by Selective Constitutive and Inducible Expression of PD-L1.
abstract: Human tumors consist of heterogeneous populations of cells with distinct marker expression and functional properties. In squamous cell carcinoma of the head and neck (SCCHN), CD44 is a well-characterized marker of a resilient subpopulation of cells associated with increased tumorigenesis, radioresistance, and chemoresistance. Evidence indicates that these cells have an immunosuppressive phenotype; however, mechanisms have been elusive.
  
  
  
  Using primary human SCCHN tumor samples and patient-derived xenografts, we examined the phenotypes of subsets of tumor cells and investigated mechanisms regulating their immunogenicity.
  
  
  
  CD44(+) cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44(-) cells when cultured with autologous CD8(+) tumor-infiltrating T cells. Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44(+) cells compared with CD44(-) cells and was associated with constitutive phosphorylation of STAT3 on CD44(+) cells. Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44(+) cells. IFNγ treatment preferentially induced even further PD-L1 expression on CD44(+) cells and was associated with enhanced IFNγ receptor expression and phosphorylation of STAT1. Finally, the decreased immunogenicity of CD44(+) cells was partially reversed by antibody blockade of the programmed death 1 (PD-1) receptor, indicating that the differences in PD-L1 expression between CD44(+) and CD44(-) cells are biologically and clinically relevant.
  
  
  
  Our findings provide a mechanism by which long-lived CD44(+) tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN. Clin Cancer Res; 22(14); 3571-81. ©2016 AACR.
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford, California. Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors: Yunqin
authors: Y
authors: Lee
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford, California. Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
authors: June Ho
authors: JH
authors: Shin
authors: Stanford Cancer Institute, Stanford, California. Program in Epithelial Biology, Stanford Cancer Institute, Stanford, California.
authors: Michelle
authors: M
authors: Longmire
authors: Stanford Cancer Institute, Stanford, California. Program in Epithelial Biology, Stanford Cancer Institute, Stanford, California.
authors: Hua
authors: H
authors: Wang
authors: Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, California.
authors: Holbrook E
authors: HE
authors: Kohrt
authors: Stanford Cancer Institute, Stanford, California. Program in Epithelial Biology, Stanford Cancer Institute, Stanford, California. Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, California. Howard Hughes Medical Institute, Stanford, California.
authors: Howard Y
authors: HY
authors: Chang
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford Cancer Institute, Stanford, California. Program in Immunology, Stanford University School of Medicine, Stanford, California. Stanford Cancer Institute, Stanford, California. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California. sunwoo@stanford.edu.
authors: John B
authors: JB
authors: Sunwoo
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D051379:Mice; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor