Expression and potential immunosuppressive role of tryptophan 2,3-dioxygenase in tumours and placental tissues

The essential amino acid tryptophan is metabolised along the kynurenine pathway by two enzymes, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was shown to be a potent immunosuppressor in a twofold way. It deprives lymphocytes of tryptophan and produces metabolites that inhibit cell proliferation and activity. In tumours, IDO1 can be either induced by pro-inflammatory stimuli in different cell types or be constitutively expressed by tumour cells. Those discoveries led to the development of IDO1 inhibitors to improve cancer immunotherapy. TDO has the same catalytic activity as IDO1, but is less active. It is primarily expressed by hepatocytes to regulate systemic tryptophan concentration. TDO2 mRNA was additionally found in tumours and the decidua (the endometrium during pregnancy). Metabolically active TDO is expressed by several tumour cell lines. In analogy to IDO1, experimental tumour models revealed an immunosuppressive function of TDO and its inhibition improved immune-mediated tumour growth control. We developed and validated highly specific mouse anti-human TDO antibodies and revealed by immunohistochemistry that TDO was expressed by different cell types in human tumours, normal tissues and the placenta. In the liver and hepatocarcinomas, TDO staining was found respectively in hepatocytes and in the tumour cells. Other normal tissues were devoid of TDO, but a high number of tumours originating from other tissues than the liver showed TDO staining in dispersed cells, ranging from 40% of kidney carcinomas to 97% of glioblastomas. Those cells were identified as pericytes and were often located in malformed vessels surrounding necrotic or haemorrhagic tumour areas in high-grade tumours. TDO-positive pericytes were also found in non-cancerous lung samples showing signs of inflammation. In the decidua and ectopic pregnancies, TDO was localised in some rare foetal pericytes and interstitial trophoblasts. Deeper analysis of glioblastoma sections revealed that TDO did not seem to impact lymphocyte infiltration. This latter result did not confirm a potential immunosuppressive role of TDO-expressing pericytes in tumours, but did not exclude an immunological impact in hepatocarcinomas. To analyse murine tissues, we replaced the constant regions of our murine antibody by rabbit constant regions. We revealed a different expression profile of TDO in murine tissues, except for livers. No tested murine tumour expressed TDO, but the decidua showed massive expression of TDO in decidual stromal cells. TDO-KO females mated with allogeneic males were as fertile as WT females, suggesting that TDO is not essential for foeto-maternal tolerance. Altogether, we showed that TDO is mostly expressed by pericytes and that the expression profiles are very different between humans and mice. Our results raise doubts about an immunosuppressive role of TDO in tumours, except for hepatocarcinomas, and suggest a possible implication in vessel formation.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201