Increased tryptophan, but not increased glucose metabolism, predict resistance of pembrolizumab in stage III/IV melanoma.
Abstract
Clinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to
show additional clinical benefit compared to PD1-alone inhibition. We reasoned that
a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically
stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing
enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed
tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan
(C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective
clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found
higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating
lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated
with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression
were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint
survival analysis of pretreatment 'high' vs. 'low' C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the 'low' C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO
expression and kynurenine production in addition to suppression of serotonin production.
High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response
and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation
may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving
the latter of an essential amino acid.
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https://hdl.handle.net/10161/29038Published Version (Please cite this version)
10.1080/2162402x.2023.2204753Publication Info
Oldan, Jorge D; Giglio, Benjamin C; Smith, Eric; Zhao, Weiling; Bouchard, Deeanna
M; Ivanovic, Marija; ... Moschos, Stergios J (2023). Increased tryptophan, but not increased glucose metabolism, predict resistance of
pembrolizumab in stage III/IV melanoma. Oncoimmunology, 12(1). pp. 2204753. 10.1080/2162402x.2023.2204753. Retrieved from https://hdl.handle.net/10161/29038.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Terence Z. Wong
Professor of Radiology
1. Anatomic/functional oncologic Imaging: SPECT/CT, PET/CT, novel PET radiotracers
2. Radiotheranostics, Radionuclide therapy of cancer, Radiation Therapy Planning 3.
Imaging biomarkers for guiding treatment strategies 4. Multicenter clinical trial
development (NCI National Clinical Trials Network)

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