title: Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia.
abstract: BACKGROUND
  ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL) and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.
  
  
  METHODS
  Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9) and healthy donors (n = 6). IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.
  
  
  RESULTS
  The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05).
  
  
  CONCLUSIONS
  ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.|Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hojjat-Farsangi
authors.affiliation: Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Jeddi-Tehrani
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.
authors.forename: Amir Hossein
authors.initials: AH
authors.lastname: Daneshmanesh
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.
authors.forename: Fariba
authors.initials: F
authors.lastname: Mozaffari
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.
authors.forename: Ali
authors.initials: A
authors.lastname: Moshfegh
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.|Department of Hematology-Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Hansson
authors.affiliation: Clinic of Hematology and Oncology, Firozgar Hospital, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Seyed Mohsen
authors.initials: SM
authors.lastname: Razavi
authors.affiliation: Clinic of Hematology and Oncology, Vali-Asr Hospital, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ramazan Ali
authors.initials: RA
authors.lastname: Sharifian
authors.affiliation: Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
authors.forename: Hodjattallah
authors.initials: H
authors.lastname: Rabbani
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.|Department of Hematology-Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.affiliation: Department of Oncology-Pathology, Immune and Gene Therapy Lab, Cancer Center Karolinska (CCK), Karolinska University Hospital Solna and Karolinska Institute, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
authors.affiliation: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.|Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
authors.forename: Fazel
authors.initials: F
authors.lastname: Shokri
mesh_terms: D000595:Amino Acid Sequence; D000906:Antibodies / Q000097:blood / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007109:Immunity / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011379:Prognosis; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D015789:HLA-A2 Antigen; D007074:Immunoglobulin G; D020381:Interleukin-17; D015848:Interleukin-5; D010455:Peptides; D007371:Interferon-gamma; D057050:Receptor Tyrosine Kinase-like Orphan Receptors