Expression of tryptophan metabolizing enzymes (TMEs) and its transporter, LAT1, in metastatic melanoma (MM): Prognostic and therapeutic implications.

Abstract

e21014 Background: The ECHO-301/KEYNOTE-252 trial failed to show clinical benefit of adding epacadostat to pembrolizumab in PD-1 inhibitor-naïve MM. We reasoned that the expression of other TMEs and/or LAT1 by melanoma cells plays a more important role. Methods: Melanoma tissues from stage III/IV pts were stained for the 4 TMEs (TPH1, TPH2, TDO2, IDO1) and LAT1 by single-color immunohistochemistry. Tissues were scored for the status of tumor-infiltrating lymphocytes (TILs) and the expression of 5 proteins separately in melanoma cells and TILs (if present). Association between protein expression, TIL status, and melanoma-specific overall survival was performed. Results: Tissues from 87 pts (stage IV, n = 25) were available. Expression of all 4 TMEs and LAT1 was significantly higher in melanoma cells compared to TILs ( p< 0.001); TPH1, TPH2, and TDO2 expression in melanoma cells was significantly higher than IDO1 (p < 0.001). Lower TPH1 expression in melanoma cells was associated with presence of TILs. Multivariate analysis using a Cox proportional hazards model that included expression of the 5 proteins in melanoma cells showed that high IDO1 was a favorable and high LAT1 expression was an adverse prognostic factor. Conclusions: Expression of TMEs and LAT1 by melanoma cells may have more important role in metastatic melanoma by depleting an essential amino acid from the tumor microenvironment. Pharmacologic targeting of TPH1/TPH2 (e.g. telotristat) may be more clinically relevant in MM as opposed to IDO1 inhibition.