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High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy


Krieg, Carsten; Nowicka, Malgorzata; Guglietta, Silvia; Schindler, Sabrina; Hartmann, Felix J; Weber, Lukas M; Dummer, Reinhard; Robinson, Mark D; Levesque, Mitchell P; Becher, Burkhard (2018). High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy. Nature Medicine, 24(2):144-153.

Abstract

Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16−HLA-DRhi monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.

Abstract

Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16−HLA-DRhi monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
04 Faculty of Medicine > Institute of Experimental Immunology
08 Research Priority Programs > Translational Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:English
Date:2018
Deposited On:26 Jan 2018 11:32
Last Modified:08 Apr 2020 22:39
Publisher:Nature Publishing Group
ISSN:1078-8956
Additional Information:European Union (EU), Horizon 2020 Erratum in: https://www.zora.uzh.ch/id/eprint/182442/
OA Status:Green
Publisher DOI:https://doi.org/10.1038/nm.4466
PubMed ID:29309059
Project Information:
  • : FunderH2020
  • : Grant ID641458
  • : Project TitleMELanoma GENetics - understanding and biomarking the genetic and immunological determinants of melanoma survival

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