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
BackgroundDespite their revolutionary success in cancer treatment over the last decades, immunotherapies encounter limitations in certain tumor types and patients. The efficacy of immunotherapies depends on tumor antigen-specific CD8 T-cell viability and functionality within the immunosuppressive tumor microenvironment, where oxygen levels are often low. Hypoxia can reduce CD8 T-cell fitness in several ways and CD8 T cells are mostly excluded from hypoxic tumor regions. Given the challenges to achieve durable reduction of hypoxia in the clinic, ameliorating CD8 T-cell survival and effector function in hypoxic condition could improve tumor response to immunotherapies.MethodsActivated CD8 T cells were exposed to hypoxia and metformin and analyzed by fluorescence-activated cell sorting for cell proliferation, apoptosis and phenotype. In vivo, metformin was administered to mice bearing hypoxic tumors and receiving either adoptive cell therapy with tumor-specific CD8 T cells, or immune checkpoint inhibitors; tumor growth was followed over time and CD8 T-cell infiltration, survival and localization in normoxic or hypoxic tumor regions were assessed by flow cytometry and immunofluorescence. Tumor oxygenation and hypoxia were measured by electron paramagnetic resonance and pimonidazole staining, respectively.ResultsWe found that the antidiabetic drug metformin directly improved CD8 T-cell fitness in hypoxia, both in vitro and in vivo. Metformin rescued murine and human CD8 T cells from hypoxia-induced apoptosis and increased their proliferation and cytokine production, while blunting the upregulation of programmed cell death protein 1 and lymphocyte-activation gene 3. This appeared to result from a reduced production of reactive oxygen species, due to the inhibition of mitochondrial complex I. Differently from what others reported, metformin did not reduce tumor hypoxia, but rather increased CD8 T-cell infiltration and survival in hypoxic tumor areas, and synergized with cyclophosphamide to enhance tumor response to adoptive cell therapy or immune checkpoint blockade in different tumor models.ConclusionsThis study describes a novel mechanism of action of metformin and presents a promising strategy to achieve immune rejection in hypoxic and immunosuppressive tumors, which would otherwise be resistant to immunotherapy.
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the rate-limiting step of tryptophan catabolism along the kynurenine pathway, which has important immuno suppressive properties, particularly in tumor cells and dendritic cells. The prominent expression of IDO1 in the placenta also suggested a role in preventing immune rejection of fetal tissues, and pharmacological inhibition of IDO1 induced abortion of allogeneic fetuses in mice. However, this was later challenged by the lack of rejection of allogeneic fetuses in IDO1-KO mice, suggesting that other mechanisms may compensate for IDO1 deficiency. Here we investigated whether TDO could contribute to feto-maternal tolerance and compensate for IDO1 deficiency in IDO1-KO mice. Expression of TDO mRNA was previously detected in placental tissues. We developed a new chimeric rabbit anti-TDO antibody to confirm TDO expression at the protein level and identify the positive cell type by immunohistochemistry in murine placenta. We observed massive TDO expression in decidual stromal cells, starting at day E3.5, peaking at day E6.5 then declining rapidly while remaining detectable until gestation end. IDO1 was also induced in decidual stromal cells, but only at a later stage of gestation when TDO expression declined. To determine whether TDO contributed to feto-maternal tolerance, we mated TDO-KO and double IDO1-TDO-KO females with allogeneic males. However, we did not observe reduced fertility. These results suggest that, despite its expression in decidual stromal cells, TDO is not a dominant mechanism of feto-maternal tolerance able to compensate for the absence of IDO1. Redundant additional mechanisms of immunosuppression likely take over in these KO mice. The massive expression of TDO during decidualization might suggest a role of TDO in angiogenesis or vessel tonicity, as previously described for IDO1.
The poverty business has recently become a frequent issue in public discourse. The Program Declaration of the Government of the Czech Republic also reflects this, as the poverty business is mentioned here in relation to the abuse of the welfare system through overpriced lodging houses. In spite of the political significance of the poverty business, the research on this issue has been scant. No attempt has even been made to clarify the meaning of this concept. This study is meant to be a first step in understanding the poverty business in the Czech context; it aims to explore how this phenomenon was represented in the Czech news media. The research was based on the theory of representation and qualitative content analysis, a method that was devised for thematic analysis of media content. The data were drawn from the Anopress IT database. Out of 1,277 texts containing the term "poverty business" and similar relevant terms, 66 texts were selected for the analysis. The analysis found that the poverty business is mainly presented as a matter of housing; however, other meanings were also identified, all of which were connected to the idea of exploitation of the poor and vulnerable segments of society. The victims of the poverty business include not only the clients of poverty entrepreneurs but also other people who were categorized according to their alleged decency or indecency. The consequences of the poverty business were seen as relating to clients, interethnic coexistence and the public administration. The main subjects identified in media communications were the state, municipality, and poverty entrepreneurs, who played the role of culprits, profiting subjects, and rectifiers. To conclude, the poverty business was represented as a highly politicized issue that concerns the misuse of housing benefits and is seen both as a socioeconomic and ethno-cultural problem. The solution to the poverty business was mostly conceived as a technical intervention into the welfare system, ignoring the agency of the victims of the poverty business.
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