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

Lusi Oka Wardhani, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Daisuke Nonaka, Keiko Nagata, Masako Kato, Yukisato Kitamura, Kazuhiko Hayashi

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

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 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 7 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 in 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 MCPyV-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.

Original languageEnglish
Pages (from-to)52-61
Number of pages10
JournalHuman Pathology
Volume84
DOIs
Publication statusPublished - Feb 2019

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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