Expression of the IDO1/TDO2-AhR pathway in tumor cells or the tumor microenvironment is associated with Merkel cell polyomavirus status and prognosis in Merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer, with approximately 80% of cases related to Merkel cell polyomavirus (MCPyV). Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) are the key rate-limiting enzymes of the tryptophan to kynurenine (KYN) metabolic pathway. With aryl hydrocarbon receptor (AhR), an intracellular transcription factor, they play a role in escaping the immunosurveillance process in several cancers. IDO1/TDO2/AhR expression associated with the MCPyV status and prognosis in MCC was investigated. Samples included 24 MCPyV-positive MCCs, 12 MCPyV-negative MCCs with squamous cell carcinoma, and seven MCPyV-negative pure MCCs. They were stained immunohistochemically with IDO1, TDO2, and AhR antibodies and analyzed. Higher IDO1 expression in MCC tumor cells was found in MCPyV-negative than in MCPyV-positive MCC (P < .001). The tumor microenvironment (TME) in MCPyV-negative MCC expressed higher TDO2 than MCPyV-positive MCC (P < .001). Kaplan-Meier and log-rank tests showed that MCC with lower IDO1 expression in tumor cells and with lower TDO2 and AhR expressions in TME had better overall survival than otherwise (P = .043, .008, and .035, respectively); lower TDO2 expression in TME was also associated with longer disease-specific survival (P = .016). This suggests that IDO1, TDO2, and AhR express differentially in tumor cells or TME and play different roles in tumorigenesis between MCPyV-positive and -negative MCC that may affect the MCC biology. Evaluating IDO1/TDO2/AhR expression is important for selecting the most likely patients with MCC for immunotherapies targeting the IDO1/TDO2-AhR pathway.

<p>TDO Promotes Hepatocellular Carcinoma Progression</p>

“…29 Similarly, glioma cells with high TDO expression grew faster and had a higher proliferation index than TDO-deficient control tumours in vivo. 12,[33][34][35] Using the P815 mouse tumour model, Pilotte found that compared to control tumours, TDO-expressing tumours grew faster and more potently inhibited local T lymphocyte proliferation. 12 In conclusion, our data show that overexpression of TDO promotes the proliferation and invasion of HCC cells in vitro and in vivo and indicate that TDO might serve as an effective biomarker for diagnosis and prognosis and a promising target for therapy in HCC.…”

Merkel cell carcinoma-derived exosome-shuttle miR-375 induces fibroblast polarization by inhibition of RBPJ and p53

“…In most cases, MCC carcinogenesis is associated with the oncogenic Merkel cell polyomavirus (MCPyV), while in the other cases, it is UV-driven [1]. MCCs are heterogeneous tumors that are often infiltrated by various immune and stromal cells [2]. While the role of tumorinfiltrating lymphocytes has been studied in detail [3][4][5], the characteristics of tumor-associated fibroblasts in the MCC microenvironment are largely unexplored.…”

Aryl Hydrocarbon Receptor Modulates Carcinogenesis and Maintenance of Skin Cancers

“…MCC is a rare and aggressive neuroendocrine skin cancer, and ~80% of patients are infected with merkel cell polyomavirus. Univariate analysis of clinical specimens revealed that a longer overall survival is achieved in the group with lower expression of tryptophan 2,3-dioxygenase 2 (TDO2) and AHR in cells surrounding the tumor (70). As TDO2 is an enzyme in the tryptophan-kynurenine metabolic pathway, the TDO2-AHR axis may play a significant role in the pathophysiology of MCC.…”