Expression of Tryptophan Metabolism Enzymes in Patients with Diffuse Large B‐cell Lymphoma and NK/T‐cell Lymphoma

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 11; pp. 12139 - 12148
• Main Authors: Guo, Dan, Wang, Yuming, Wu, Xunyao, Gao, Yike, Wang, Anqi, Zhang, Zixin, Zhao, Kun, Wang, Xiaoxi, Liu, Meiyu, Zhang, Yaran, Li, Mei, Chen, Rui, Sun, Jian, Zhang, Yan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.06.2023; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; B-cell lymphoma; Biopsy; diffuse large B‐cell lymphoma; Enzyme inhibitors; Enzymes; Immunohistochemistry; Immunotherapy; Ligands; Liver cancer; Lymphocytes B; Lymphocytes T; Lymphoma; Medical prognosis; Metabolism; Natural killer cells; natural killer/T‐cell lymphoma; Patients; PD-L1 protein; programmed death‐ligand 1; T-cell lymphoma; Tryptophan; tryptophan metabolism; Tumor microenvironment; Tumors; programmed death-ligand 1; diffuse large B-cell lymphoma; immunohistochemistry; tryptophan metabolism; natural killer/T-cell lymphoma
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.5903

Background Metabolites of tryptophan (Trp) metabolism in the tumor microenvironment play crucial immunosuppressive roles in various cancers. However, the role of Trp metabolism in diffuse large B‐cell lymphoma (DLBCL) or natural killer/T‐cell lymphoma (NK/TCL) remains unelucidated. Methods We investigated the potential role of Trp metabolism in a cohort of 43 patients with DLBCL and 23 with NK/TCL. We constructed tissue microarrays and performed in situ staining of Trp‐catabolizing enzymes and PD‐L1 using immunohistochemistry (IHC). Results We observed 14.0% positive staining of IDO1 in DCBCL and 60.9% in NK/TCL; 55.8% of IDO2 in DCBCL and 95.7% in NK/TCL; 79.1% of TDO2 in DCBCL and 43.5% in NK/TCL; 29.7% of IL4I1 in DCBCL and 39.1% in NK/TCL. However, IDO1, IDO2, TDO2, and IL4I1 positivity did not significantly differ between PD‐L1+ and PD‐L1− biopsy tissue samples of NK/TCL; nonetheless, a positive correlation of IDO1 (r = 0.87, p < 0.001), IDO2 (r = 0.70, p < 0.001), TDO2 (r = 0.63, p < 0.001), and IL4I1 (r = 0.53, p < 0.05) with PD‐L1 expression was observed in the TCGA‐DLBCL dataset. Finally, immunohistochemical (IHC) analysis revealed the lack of superior prognostic effect with higher expression of Trp enzymes in DLBCL and NK/TCL. Furthermore, IDO1, IDO2, TDO2, and IL4I1 expression, as well as survival rates, did not significantly differ across all groups in the TCGA‐DLBCL cohort. Conclusion Collectively, our findings provide novel insights into the enzymes involved in Trp metabolism in DLBCL and NK/TCL and their association with PD‐L1 expression, which offers potential strategies to combine Trp‐metabolism enzyme inhibitors with anti‐PD‐L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment. The degradation of Tryptophan to Kynurenine is catabolized by tryptophan enzymes, including IDO1, IDO2, TDO2, and IL4I1, which up‐regulate PD‐L1 expression and promote tumor suppressive microenvironment in various cancers. In the present study, we constructed tissue microarrays and performed in situ staining of Trp‐catabolizing enzymes and PD‐L1 using immunohistochemistry in the diffuse large B‐cell lymphoma (DLBCL) or natural killer/T‐cell lymphoma (NK/TCL). We provide potential strategies for Trp metabolism enzyme inhibitors in combination with anti‐PD‐L1 or other immunotherapeutic strategies in clinical DLBCL or NK/TCL treatment.