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 SUV_max of the hottest tumor lesion per patient revealed that the ‘low’ C11-AMT SUV_max was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUV_max. 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.

KEYWORDS:

• IDO1
• immunometabolism
• metastatic melanoma
• TPH1
• tryptophan

Abbreviations

Trp, tryptophan; IDO1, indoleamine 2,3-dioxygenase; TDO2, tryptophan 2,3-dioxygenase-2; MM, metastatic melanoma; TPH, tryptophan hydroxylase; TMEs, tryptophan-metabolizing enzymes; LAT1/SLC7A5, Large neutral amino acid transporter small subunit-1; TILs, tumor-infiltrating lymphocytes; OS, overall survival; CLA, cell-line array; ICC, immunocytochemistry; TMA, tissue microarray; IHC, immunohistochemistry; SOC, standard of care; UNC-CH, University of North Carolina at Chapel Hill; PET, positron emission photography; FDG, fluorodeoxyglucose; CT, computerized tomography; IV, intravenous; RECIST, OR, odds ratio; 95 CI, 95% confidence intervals.

Acknowledgments

We thank the patients and their families for participating in the LCCC1531 trial.

Disclosure statement

Funding for the LCCC1531 trial was provided by Merck & Co., Inc.

Data availability statement

The data that support the findings of this study are available from the corresponding author, SJM, upon reasonable request.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2204753.

Additional information

Funding

This work was supported by The National Cancer Institute Cancer Clinical Investigator Team Leadership Award (5P30CA016086-38, SJM), NCI 1 R01 CA233904-01 (ZL and SJM), and Merck & Co., Inc (SJM and ZL).