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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

Abstract

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.

Keywords

Cancer immunotherapy Cancer metabolomics Renal cell carcinoma Urothelial cancer 

Abbreviations

CI

Confidence interval

CPI

Checkpoint inhibitor

CR

Complete remission

FAO

Fatty acid oxidation

FDG-PET

Fluorodeoxyglucose positron emission tomography

GLC

Glucose

GPL

Glycerophospholipid

HR

Hazard ratio

LCFA

Long-chain fatty acid

LMM

Linear mixed effects model

LOD

Limit of detection

MS

Mass spectroscopy

NMR

Nuclear magnetic resonance

PC

Phosphatidylcholine

PD

Progressive disease

PPAR-α

Peroxisome proliferation-activated receptor α

PR

Partial remission

RCC

Renal cell carcinoma

ROC

Receiver operating characteristic

SD

Stable disease

SLC27A2

Solute carrier family 27 member 2 gene

sGPL

Saturated GPL

SM

Sphingomyelin

SVM

Support vector machine

TCGA

The Cancer Genome Atlas

TMB

Tumor mutational burden

tSNE

T-distributed stochastic neighbor embedding

UC

Urothelial carcinoma

uGPL

Unsaturated GPL

VLCFA

Very long-chain fatty acid

Notes

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.

Funding

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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