title: The proportion of circulating CD45RO+CD8+memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab.
abstract: Immune checkpoint blockade (ICB) has been a breakthrough in the treatment of metastatic melanoma. But with only about 20-40% long-term responders and severe side-effects in about 12-17%, finding predictive markers for treatment response is of great interest.
  
  
  
  We prospectively assessed clinical data, haematologic parameters and freshly isolated peripheral blood mononuclear cells of 30 patients treated with ipilimumab (n = 21) and pembrolizumab (n = 9) prior to the first 4 cycles with ICB and before the first tumour assessment.
  
  
  
  We discovered that the baseline levels of CD45RO+CD8+T cells significantly differed among the patients. Thirteen (43%) of our patients had normal baseline levels of CD45RO+CD8+T cells, whereas 17 (57%) patients were low on CD45RO+CD8+T cells. The baseline levels of CD45RO+CD8+T cells correlated significantly with the response to ipilimumab but not pembrolizumab. Patients with baseline levels of lower/equal 25% of CD45RO+CD8+T cells did not respond to treatment with ipilimumab. Phenotyping the CD8+T cells in patients treated with ipilimumab revealed an activated HLA-DR+CD25-phenotype, implying antigen non-specific stimulation. The levels of the HLA-DR+CD25-CD8+T cells were significantly higher in patients with a normal baseline of CD45RO+CD8+T cells and even increased significantly during treatment. Furthermore, proliferation of melanoma antigen recognized by T cells 1 (MART-1)-specific CD8+T cells was not observed. Patients with normal baseline levels of CD45RO+CD8+T cells showed a significant longer overall survival when treated with ipilimumab but not pembrolizumab.
  
  
  
  Patients with normal baseline levels of CD45RO+CD8+T cells respond significantly more frequently to treatment with ipilimumab and the CD8+T cells appear to be antigen non-specifically activated. The baseline level of CD45RO+CD8+T cells represents a promising factor as biomarker for the prediction of the response to ipilimumab.
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany. Electronic address: Julia.Tietze@med.uni-muenchen.de.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Tietze
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Angelova
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
authors.forename: Markus V
authors.initials: MV
authors.lastname: Heppt
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reinholz
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, 3301 C Street, Sacramento, CA 95816, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
authors.affiliation: Department of Internal Medicine, University Hospital Munich (LMU), Ziemssenstr. 1, 80336 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ruzicka
authors.affiliation: Department of Dermatology and Allergy, University Hospital Munich (LMU), Frauenlobstr. 9-11, 80337 Munich, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006801:Humans; D000074324:Ipilimumab; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000074324:Ipilimumab; C582435:pembrolizumab; D017493:Leukocyte Common Antigens
keywords: CD45RO(+)CD8(+) T cells; HLA-DR(+)CD25(−)CD8(+) phenotype; Immune checkpoint blockade; Ipilimumab; Melanoma; Pembrolizumab; Predictive marker