Serum very long-chain fatty acid-containing lipids predict response to immune checkpoint inhibitors in urological cancers
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.
KeywordsCancer immunotherapy Cancer metabolomics Renal cell carcinoma Urothelial cancer
Fatty acid oxidation
Fluorodeoxyglucose positron emission tomography
Long-chain fatty acid
Linear mixed effects model
Limit of detection
Nuclear magnetic resonance
Peroxisome proliferation-activated receptor α
Renal cell carcinoma
Receiver operating characteristic
Solute carrier family 27 member 2 gene
Support vector machine
The Cancer Genome Atlas
Tumor mutational burden
T-distributed stochastic neighbor embedding
Very long-chain fatty acid
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.
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.
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