Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers

Abstract

Tryptophan catabolism is used by tumors to resist immune attack. It can be catalyzed by indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). IDO1 is frequently expressed in tumors and has been widely studied as a potential therapeutic target to reduce resistance to cancer immunotherapy. In contrast, TDO expression in tumors is not well characterized. Several human tumor cell lines constitutively express enzymatically active TDO. In human tumor samples, TDO expression has previously been detected by transcriptomics, but the lack of validated antibodies has precluded detection of the TDO protein and identification of TDO-expressing cells. Here, we developed novel TDO-specific monoclonal antibodies and confirmed by immunohistochemistry the expression of TDO in the majority of human cancers. In all hepatocarcinomas (10/10), TDO was expressed by most tumor cells. Some glioblastomas (10/39) and kidney carcinomas (1/10) also expressed TDO in tumor cells themselves but only in focal tumor areas. In addition, all cancers tested contained foci of nontumoral TDO-expressing cells, which were identified as pericytes by their expression of PDGFRβ and their location in vascular structures. These TDO-expressing pericytes belonged to morphologically abnormal tumor vessels and were found in high-grade tumors in the vicinity of necrotic or hemorrhagic areas, which were characterized by neoangiogenesis. We observed similar TDO-expressing pericytes in inflammatory pulmonary lesions containing granulation tissue, and in chorionic villi, two tissue types that also feature neoangiogenesis. Our results confirm TDO as a relevant immunotherapeutic target in hepatocellular carcinoma and suggest a proangiogenic role of TDO in other cancer types. See article by Schramme et al., p. 32

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

“…10 TDO was first found to be expressed in human glioma cells and then in many human tumours, such as hepatocarcinomas, melanomas, bladder carcinomas, breast cancer, and other tumour tissues, where it regulates the tumour immune response. 11 Pharmacological inhibition of TDO prevents tumoural immune resistance and promotes tumour rejection. 12,13 TDO overexpression results in resistance to immune rejection by T cells in a P815 mouse tumour model, and mice grafted with TDO-overexpressing tumour cells developed progressive tumours and died faster.…”

Different effects of tryptophan 2,3-dioxygenase inhibition on SK-Mel-28 and HCT-8 cancer cell lines

“…The inhibition of endothelial proliferation suggests that TDO may be involved in angiogenesis. Recently, it has been discovered that some type of cancers (such as hepatocarcinoma, glioblastoma, bladder carcinoma) contained foci of non-tumoral TDO-expressing cells, which were identified as pericytes, that were found in high-grade tumours close to necrotic or hemorrhagic areas, characterized by neoangiogenesis (Hoffmann et al 2020 ). Although these important observations on IDO1, no data are available on TDO and angiogenesis and on its cooperation with IDO1 on melanoma progression.…”

Circular RNA circZNF566 promotes hepatocellular carcinoma progression by sponging miR-4738-3p and regulating TDO2 expression

“…Recently, it has been reported TDO is expressed in human tumors, such as human glioma cells, hepatocarcinomas, breast cancer, and some other tumors. In fact, of all cancers, TDO2 is most highly expressed in HCC [19][20][21] . TDO regulates tumor activity and the immune response via the Try-Kyn-aryl hydrocarbon receptor (Ahr) pathway, and similar research has also been reported in breast cancer 22,23 .…”