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.