Publikationsdatum:
2014-11-28
Beschreibung:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246418/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246418/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tumeh, Paul C -- Harview, Christina L -- Yearley, Jennifer H -- Shintaku, I Peter -- Taylor, Emma J M -- Robert, Lidia -- Chmielowski, Bartosz -- Spasic, Marko -- Henry, Gina -- Ciobanu, Voicu -- West, Alisha N -- Carmona, Manuel -- Kivork, Christine -- Seja, Elizabeth -- Cherry, Grace -- Gutierrez, Antonio J -- Grogan, Tristan R -- Mateus, Christine -- Tomasic, Gorana -- Glaspy, John A -- Emerson, Ryan O -- Robins, Harlan -- Pierce, Robert H -- Elashoff, David A -- Robert, Caroline -- Ribas, Antoni -- K08 AI091663/AI/NIAID NIH HHS/ -- P01 CA168585/CA/NCI NIH HHS/ -- P30 CA16042/CA/NCI NIH HHS/ -- R01 CA170689/CA/NCI NIH HHS/ -- U54 CA119347/CA/NCI NIH HHS/ -- UL1TR000124/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Nov 27;515(7528):568-71. doi: 10.1038/nature13954.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] University of California Los Angeles (UCLA), Los Angeles, California 90095, USA [2] Jonsson Comprehensive Cancer Center, Los Angeles, California 90095, USA. ; University of California Los Angeles (UCLA), Los Angeles, California 90095, USA. ; Merck &Co, Palo Alto, California 94304, USA. ; Gustave Roussy and INSERM U981, Villejuif, Paris Sud, France. ; Adaptive Biotechnologies, Seattle, Washington 98102, USA. ; 1] Adaptive Biotechnologies, Seattle, Washington 98102, USA [2] Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428505" target="_blank"〉PubMed〈/a〉
Schlagwort(e):
Adaptive Immunity/*immunology
;
Aged
;
Aged, 80 and over
;
Biomarkers
;
CD8-Positive T-Lymphocytes/cytology/*immunology
;
Cell Proliferation
;
Female
;
Gene Expression Regulation, Neoplastic
;
Humans
;
*Immunotherapy
;
Male
;
Melanoma/diagnosis/immunology/pathology/*therapy
;
Middle Aged
;
*Models, Biological
;
Multivariate Analysis
;
Programmed Cell Death 1 Receptor/antagonists & inhibitors/genetics/immunology
;
Treatment Outcome
Print ISSN:
0028-0836
Digitale ISSN:
1476-4687
Thema:
Biologie
,
Chemie und Pharmazie
,
Medizin
,
Allgemeine Naturwissenschaft
,
Physik
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