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+CD16HLA-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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Acknowledgements

We thank V. Tosevski and T.M. Brodie (mass cytometry core facility, University of Zurich), A. Langer (Department of Dermatology, University of Zurich), and C. Beisel and K. Eschbach (Genomics Facility, ETH Basel) for excellent technical assistance and N. Nunes, B. Chatterjee, E. Terskikh, and C. Gujer (all from the Institute of Experimental Immunology, University Zurich), A. Zollinger (Swiss Institute of Bioinformatics, Lausanne), all members of the COST Action BM1404 Mye-EUNITER (http://www.mye-euniter.eu), and P. Cheng (University of Zurich) for discussions. We also thank C. Guglietta for graphical design and layout. This work received funding from the University Research Priority Program (URPP) in Translational Cancer Research (C.K.), the Swiss National Science Foundation (grants 310030_146130 and 316030_150768; B.B.), the European Union FP7 project ATECT (B.B.), and the European Training Network MELGEN (M.P.L.).

Author information

Author notes

    • Carsten Krieg

    Present address: Department of Microbiology and Immunology and Department of Dermatology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.

    • Mitchell P Levesque
    •  & Burkhard Becher

    These authors jointly directed this work.

Affiliations

  1. Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

    • Carsten Krieg
    • , Felix J Hartmann
    •  & Burkhard Becher
  2. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.

    • Malgorzata Nowicka
    • , Lukas M Weber
    •  & Mark D Robinson
  3. Swiss Institute of Bioinformatics (SIB), University of Zurich, Zurich, Switzerland.

    • Malgorzata Nowicka
    • , Lukas M Weber
    •  & Mark D Robinson
  4. Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.

    • Silvia Guglietta
  5. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.

    • Sabrina Schindler
    • , Reinhard Dummer
    •  & Mitchell P Levesque

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Contributions

C.K., M.P.L., and B.B. conceived the study and analyzed data; C.K., S.G., and B.B. designed and performed the experiments; F.J.H. and S.G. assisted with the experiments; S.S., R.D., and M.P.L. provided clinical samples and performed statistical analyses of clinical parameters; R.D. and M.P.L. analyzed histology; M.N., L.M.W., and M.D.R. provided analysis algorithms and analyzed data; C.K. and S.G. wrote the manuscript; M.P.L., M.D.R., and B.B. edited the manuscript; and all authors read and gave final approval to submit the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Carsten Krieg or Mitchell P Levesque or Burkhard Becher.

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https://doi.org/10.1038/nm.4466

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