Tryptophan 2,3-dioxygenase in tumor cells is associated with resistance to immunotherapy in renal cell carcinoma |
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| Authors: | Makoto Sumitomo Kiyoshi Takahara Kenji Zennami Tomomi Nagakawa Yasuhiro Maeda Kazuya Shiogama Yasuko Yamamoto Yoshinari Muto Takuhisa Nukaya Masashi Takenaka Kosuke Fukaya Manabu Ichino Hitomi Sasaki Kuniaki Saito Ryoichi Shiroki |
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| Affiliation: | 1. Fujita Cancer Center, Fujita Health University, Toyoake, Japan;2. Department of Urology, School of Medicine, Fujita Health University, Toyoake, Japan;3. Research Promotion and Support Headquarters, Center for Joint Research Facilities Support, Fujita Health University, Toyoake, Japan;4. Department of Pathology, School of Health Sciences, Fujita Health University, Toyoake, Japan;5. Department of Disease Control and Prevention, Fujita Health University, Toyoake, Japan |
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| Abstract: | Indoleamine 2,3-dioxygenase 1 (IDO1) is a key enzyme associated with immunomodulation through its regulation of the tryptophan-kynurenine (Kyn) pathway in advanced cancers, including metastatic renal cell carcinoma (mRCC). However, the failure of IDO1 inhibitors when used in combination with immune checkpoint inhibitors (ICIs), as observed in clinical trials, raises a number of questions. This study aimed to investigate the association of tryptophan 2,3-dioxygenase (TDO) and IDO1 with cancer development and resistance to immunotherapy in patients with RCC. In our analysis of RCC tissue samples, tissue Kyn levels were elevated in advanced-stage RCC and correlated well with TDO expression levels in RCC tumor cells. In patients with mRCC, TDO rather than IDO1 was expressed in RCC tumor cells, showing a strong association with Kyn expression. Furthermore, immunohistochemical staining of TDO was strongly associated with the staining intensity of forkhead box P3, as well as ICI therapy response and survival in patients with mRCC. Our study is the first to show that TDO expression in tumor tissues is associated with progression and survival, confirming its potential as a predictive biomarker of primary resistance to immunotherapy in patients with mRCC. Our findings suggest that strategies aimed at inhibiting TDO, rather than IDO1, in combination with ICI therapy may aid in the control of mRCC progression. |
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| Keywords: | biomarker IDO1 immune checkpoint inhibitor renal cell carcinoma TDO |
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