title: Clinical Significance of Circulating CD33+CD11b+HLA-DR- Myeloid Cells in Patients with Stage IV Melanoma Treated with Ipilimumab.
abstract: OBJECTIVE
  High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33+CD11b+HLA-DR-MDSCs could be used as immune system monitoring biomarkers to predict response and survival of patients with stage IV melanoma treated with anti-CTLA4 (ipilimumab) therapy.
  
  
  METHODS
  Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33+CD11b+HLA-DR-MDSC percentage, NO-, and hROS levels by flow cytometry. We determined whether MDSC levels and suppressive features detected before anti-CTLA4 therapy correlate with the patients' response and overall survival (OS).
  
  
  RESULTS
  Patients with melanoma had significantly higher levels of circulating CD33+CD11b+HLA-DR-MDSCs with suppressive phenotype when compared with HDs. Low levels of MDSCs before CTLA-4 therapy correlated with an objective clinical response, long-term survival, increased CD247 expression in T cells, and an improved clinical status. No predictive impact was observed for lactate dehydrogenase (LDH). Kaplan-Meier and log-rank tests performed on the 56 patients showed that the presence of more than 55.5% of circulating CD33+CD11b+out of the HLA-DR-cells, were associated with significant short OS (P < 0.003), a median of 6.5 months, in comparison with the group showing lower MDSC frequencies, with a median survival of 15.6 months.
  
  
  CONCLUSIONS
  Our study suggests the use of CD33+CD11b+HLA-DR-cells as a predictive and prognostic biomarker in patients with stage IV melanoma treated with anti-CTLA4 therapy. This monitoring system may aid in the development of combinatorial modalities, targeting the suppressive environment in conjunction with iplimumab, toward facilitating better disease outcomes. Clin Cancer Res; 22(23); 5661-72. ©2016 AACR.
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, BioMedical Research institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Sade-Feldman
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, BioMedical Research institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Julia
authors.initials: J
authors.lastname: Kanterman
authors.affiliation: ImProDia Ltd., Herzliya Pituah, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Klieger
authors.affiliation: ImProDia Ltd., Herzliya Pituah, Israel.
authors.forename: Eliran
authors.initials: E
authors.lastname: Ish-Shalom
authors.affiliation: ImProDia Ltd., Herzliya Pituah, Israel.
authors.forename: Mizrahi
authors.initials: M
authors.lastname: Olga
authors.affiliation: The Lautenberg Center for General and Tumor Immunology, BioMedical Research institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: Amijai
authors.initials: A
authors.lastname: Saragovi
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Organization, Jerusalem, Israel.
authors.forename: Hani
authors.initials: H
authors.lastname: Shtainberg
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Organization, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Lotem
authors.affiliation: Sharett Institute of Oncology, Hadassah Medical Organization, Jerusalem, Israel. michalb@ekmd.huji.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Baniyash
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood; D039481:CD11b Antigen / Q000097:blood*; D060908:CTLA-4 Antigen / Q000097:blood; D005260:Female; D006684:HLA-DR Antigens / Q000097:blood*; D006801:Humans; D000074324:Ipilimumab / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009367:Neoplasm Staging / Q000379:methods; D011379:Prognosis; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000097:blood*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D039481:CD11b Antigen; C571163:CD33 protein, human; D060908:CTLA-4 Antigen; D006684:HLA-DR Antigens; C509295:ITGAM protein, human; D000074324:Ipilimumab; D063268:Sialic Acid Binding Ig-like Lectin 3