title: T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker.
abstract: Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and next-generation T- and B-cell immunosequencing (TCRß/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD-1 on all T-cell subsets after the first dose of the antibody. Both T- and B-cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T-cell compartments, as well as of naïve B- and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T-cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD-1 inhibitor. No disease stabilizations were observed without clonal T-cell space diversification. Our data show for the first time a clear impact of PD-1 targeting not only on circulating T-cells, but also on B-lineage cells, shedding light on the complexity of the anti-tumor immune response. Liquid biopsy T-cell next-generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies.
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nuray
authors.initials: N
authors.lastname: Akyüz
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Brandt
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Stein
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schliffke
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Mährle
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Quidde
authors.affiliation: Hämatologisch-Onkologische Praxis Eppendorf (HOPE), Hamburg, Germany.
authors.forename: Eray
authors.initials: E
authors.lastname: Goekkurt
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Loges
authors.affiliation: Department of Dermatology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haalck
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christopher Thomas
authors.initials: CT
authors.lastname: Ford
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Asemissen
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thiele
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Radloff
authors.affiliation: LYTIQ GmbH, Paderborn, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Thenhausen
authors.affiliation: LYTIQ GmbH, Paderborn, Germany.|Analytische Informationssysteme und Business Intelligence, Universität Paderborn, Paderborn, Germany.
authors.forename: Artus
authors.initials: A
authors.lastname: Krohn-Grimberghe
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bokemeyer
authors.affiliation: Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum/UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mascha
authors.initials: M
authors.lastname: Binder
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000276:immunology; D000951:Antigens, Neoplasm / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D001706:Biopsy; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1; biomarker; immune checkpoint inhibition; immunoprofiling; next-generation sequencing