Introduction: Indoleamine-2,3-dioxygense (IDO) is the enzyme that catalyzes the first step of tryptophan catabolism pathway in humans. It is known to impose a local immunosuppressive effect due to the hypersensitivity of lymphocytes to either the depletion of tryptophan itself or the accumulation of the metabolic intermediates of its catabolism pathway. Transforming growth factor beta (TGF-β) and interferon gamma (IFN-γ) are well-recognized positive regulators of IDO; both of them up-regulate IDO1 gene expression. Physiologically, IDO prevents the rejection of allogeneic fetus in pregnant females; yet tumors are known to overexpress IDO to avoid the immune response of the host. This study analyzes the prognostic significance of the three proteins in one of the strongest immunity-involved human tumors - the malignant melanoma (MM).
Material and methods: The material included paraffin-embedded specimen of 78 completely resected stage II-III primary skin MMs and 28 lymph nodes with metastases. Immunohistochemical staining was used to detect IDO directly. The material was not suitable for direct cytokine detection, therefore for TGF-β and IFN-γ immunohistochemical staining of their receptors was used (TGF-βR1 and IFN-γR1, respectively). A 4-step semiquantitative scale was used to assess the expression of the proteins (0/+/++/+++). For IDO, the pathologist's assessment was additionally validated by a computer-aided algorithm, which yielded percentage scores of staining intensity. The results were co-related to the clinical variables and the patient outcome, measured as disease-free (DFS), distant metastasis (or inoperable locoregional recurrence)-free (MFS) and overall survival (OS). Mann-Whitney and Wilcoxon tests were used for group comparison and Kaplan-Meier and Cox models were used for survival analysis.
Results: Median follow-up of the patients was 58.8 months (range: 5.6 – 129.5). IDO expression was significantly higher in patients who developed bone metastases compared to ones with other metastatic sites (p=0.04). On the contrary, IFN-γR1 expression levels were higher in patients who did not experience disease dissemination during the follow up than in those who did (p=0.008). High IFN-γR1 expression was associated with better median survival times (OS and MFS of +++ vs ++/+: 94 vs 38 months, p=0.01 and 93 vs 31 months, p=0.005, respectively) as well as with a reduced risk of death and dissemination in multivariate models (HR=0.48, p=0.004 and HR=0.49, p=0.003, respectively). Low IDO expression had a similar effect on unfavorable events' risk reduction, but only significant in patients with no initial lymph node involvement (HR=2.73, p=0.002; HR=4.2, p=0.0003 and HR=2.71, p=0.001 for OS, MFS and DFS, respectively). Mutual correlations of the expression levels of all proteins were only observed between TGF-βR1 and IFN-γR1 in metastatic lymph nodes (R=0.53, p<0.05). In an analysis of change in protein expression in matched pairs of skin tumors and metastatic lymph nodes from the same patient significant differences were observed for TGF-βR1 (p=0.004). A strong correlation was observed between semiquantitative and computer-aided IDO expression scores (R=0.62, p<0.05).
Conclusions: High IFN-γR1 expression is associated with better OS and MFS in melanoma patients independently of their tumor's clinical stage. Low IDO expression in N0 patients is associated with a reduced risk of death, dissemination and recurrence. TGF-βR1 and IFN-γR1 are moderately positively correlated in lymph node metastases and TGF-βR1 expression is different in skin tumors and lymph nodes of the same patient. Computer-aided image analysis is a promising validation method for immunohistochemical analysis and should be further developed.
Citation Format: Maciej J. Pelak, Dariusz Lange, Barbara Nikiel, Katarzyna M. Pecka, Miroslaw Snietura. Indoleamine-2,3-dioxygense, the receptors for transforming growth factor beta and interferon gamma in resected melanoma: The presence, co-relation to the clinical variables and prognostic value. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B044.
- ©2016 American Association for Cancer Research.