title: PD-1 Blockade Expands Intratumoral Memory T Cells.
abstract: Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single-cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells significantly increased in patients' biopsies taken on treatment. The percentage of cells with a regulatory T-cell phenotype, monocytes, and natural killer cells did not change while on PD-1 blockade therapy. CD8(+) memory T cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4(+) effector memory T cells significantly decreased on treatment, whereas CD4(+) effector T cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 was detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and myeloid-derived suppressor cells in tumors, with the CD8(+) effector memory T-cell subset being the major T-cell phenotype expanded in patients with a response to therapy.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California. Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California. Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. bcomin@mednet.ucla.edu aribas@mednet.ucla.edu.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Daniel Sanghoon
authors.initials: DS
authors.lastname: Shin
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Jesse
authors.initials: J
authors.lastname: Zaretsky
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Juliet
authors.initials: J
authors.lastname: Frederiksen
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Cornish
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Earl
authors.initials: E
authors.lastname: Avramis
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seja
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Kivork
authors.affiliation: CytoAnalysis, Denver, Colorado.
authors.forename: Janet
authors.initials: J
authors.lastname: Siebert
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Paula
authors.initials: P
authors.lastname: Kaplan-Lefko
authors.affiliation: Department of General Internal Medicine and Healthy Services Research, University of California Los Angeles, Los Angeles, California.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: John A
authors.initials: JA
authors.lastname: Glaspy
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. Department of Medicine, Division of Dermatology. University of California Los Angeles, Los Angeles, California.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Tumeh
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.affiliation: Departments of Biological Sciences and Systems Biology, Columbia University, New York, New York.
authors.forename: Dana
authors.initials: D
authors.lastname: Pe'er
authors.affiliation: Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, Los Angeles, California. bcomin@mednet.ucla.edu aribas@mednet.ucla.edu.
authors.forename: Begoña
authors.initials: B
authors.lastname: Comin-Anduix
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000556:secondary; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C582435:pembrolizumab