title: PD-1 blockade induces responses by inhibiting adaptive immune resistance.
abstract: Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8(+) T cells (termed adaptive immune resistance). Here we show that pre-existing CD8(+) T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8(+) T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.
authors.affiliation: 1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Tumeh
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Harview
authors.affiliation: Merck &Co, Palo Alto, California 94304, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: I Peter
authors.initials: IP
authors.lastname: Shintaku
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Emma J M
authors.initials: EJ
authors.lastname: Taylor
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Lidia
authors.initials: L
authors.lastname: Robert
authors.affiliation: 1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Marko
authors.initials: M
authors.lastname: Spasic
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Henry
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Voicu
authors.initials: V
authors.lastname: Ciobanu
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Alisha N
authors.initials: AN
authors.lastname: West
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Carmona
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Kivork
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seja
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Cherry
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Gutierrez
authors.affiliation: University of California Los Angeles (UCLA), Los Angeles, California 90095, USA.
authors.forename: Tristan R
authors.initials: TR
authors.lastname: Grogan
authors.affiliation: Gustave Roussy and INSERM U981, Villejuif, Paris Sud, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Gustave Roussy and INSERM U981, Villejuif, Paris Sud, France.
authors.forename: Gorana
authors.initials: G
authors.lastname: Tomasic
authors.affiliation: 1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Glaspy
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington 98102, USA.
authors.forename: Ryan O
authors.initials: RO
authors.lastname: Emerson
authors.affiliation: 1] Adaptive Biotechnologies, Seattle, Washington 98102, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Merck &Co, Palo Alto, California 94304, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Pierce
authors.affiliation: 1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Elashoff
authors.affiliation: Gustave Roussy and INSERM U981, Villejuif, Paris Sud, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: 1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D008954:Models, Biological; D015999:Multivariate Analysis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D061026:Programmed Cell Death 1 Receptor