Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers

  • Andreas Mock
  • Stefanie Zschäbitz
  • Romy Kirsten
  • Matthias Scheffler
  • Barbara Wolf
  • Christel Herold-Mende
  • Rebecca Kramer
  • Elena Busch
  • Maximilian Jenzer
  • Dirk Jäger
  • Carsten GrüllichEmail author
Original Article


Checkpoint inhibitors (CPI) have significantly changed the therapeutic landscape of oncology. We adopted a non-invasive metabolomic approach to understand immunotherapy response and failure in 28 urological cancer patients. In total, 134 metabolites were quantified in patient sera before the first, second, and third CPI doses. Modeling the association between metabolites and CPI response and patient characteristics revealed that one predictive metabolite class  (n = 9/10) were very long-chain fatty acid-containing lipids (VLCFA-containing lipids). The best predictive performance was achieved through a multivariate model, including age and a centroid of VLCFA-containing lipids prior to first immunotherapy (sensitivity: 0.850, specificity: 0.825, ROC: 0.935). We hypothesize that the association of VLCFA-containing lipids with CPI response is based on enhanced peroxisome signaling in T cells, which results in a switch to fatty acid catabolism. Beyond use as a novel predictive non-invasive biomarker, we envision that nutritional supplementation with VLCFA-containing lipids might serve as an immuno sensitizer.


Cancer immunotherapy Cancer metabolomics Renal cell carcinoma Urothelial cancer 



Confidence interval


Checkpoint inhibitor


Complete remission


Fatty acid oxidation


Fluorodeoxyglucose positron emission tomography






Hazard ratio


Long-chain fatty acid


Linear mixed effects model


Limit of detection


Mass spectroscopy


Nuclear magnetic resonance




Progressive disease


Peroxisome proliferation-activated receptor α


Partial remission


Renal cell carcinoma


Receiver operating characteristic


Stable disease


Solute carrier family 27 member 2 gene


Saturated GPL




Support vector machine


The Cancer Genome Atlas


Tumor mutational burden


T-distributed stochastic neighbor embedding


Urothelial carcinoma


Unsaturated GPL


Very long-chain fatty acid


Author contributions

Conception of the work: SZ, CG; funding acquisition: CG, DJ; sample collection and processing: RK, EC, MJ, AM; metabolomic analysis: MS, BW, AM; data collection and data analysis: AM, SZ, CG, CH; manuscript writing/editing: AM, SZ, GC; critical revision of the manuscript: DJ, MS, BW, RK, RK, EB, MJ; final approval: all the authors.


The National Center for Tumor Diseases (NCT) is supported by the German Cancer Research Center (DKFZ), the University Hospital Heidelberg in cooperation with the Medical Faculty Heidelberg, and by the German Cancer Aid (Deutsche Krebshilfe). This project was supported by the NCT Elevator Pitch 2015.

Compliance with ethical standards

Conflict of interest

Matthias Scheffler and Barbara Wolf are employed by BIOCRATES Life Sciences AG. The other authors have declared no competing interests.

Ethical approval and ethical standards

The ethics committee of the University of Heidelberg, Germany approved the study design (S023/2016). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

All patients provided written informed consent. Informed consent included the permission to take blood samples for research purposes and the use of their anonymized clinical data. Any patient identifiable information was excluded from further sample handling and data processing.

Supplementary material

262_2019_2428_MOESM1_ESM.pdf (90 kb)
Supplementary material 1 (PDF 89 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Andreas Mock
    • 1
  • Stefanie Zschäbitz
    • 1
  • Romy Kirsten
    • 2
  • Matthias Scheffler
    • 3
  • Barbara Wolf
    • 3
  • Christel Herold-Mende
    • 4
  • Rebecca Kramer
    • 1
  • Elena Busch
    • 1
  • Maximilian Jenzer
    • 1
  • Dirk Jäger
    • 1
  • Carsten Grüllich
    • 1
    • 5
    Email author
  1. 1.Department of Medical Oncology, National Center for Tumor Diseases (NCT) HeidelbergHeidelberg University HospitalHeidelbergGermany
  2. 2.Liquid Biobank, National Center for Tumor Diseases (NCT) HeidelbergHeidelberg University HospitalHeidelbergGermany
  3. 3.BIOCRATES Life Sciences AGInnsbruckAustria
  4. 4.Division of Experimental Neurosurgery, Department of NeurosurgeryHeidelberg University HospitalHeidelbergGermany
  5. 5.Department of UrologyDresden University HospitalDresdenGermany

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