Context: Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxido-reductase that catalyzes tryptophan degradation to kynurenine. In cancer, it appears to exert an immunosuppressive function as part of an acquired mechanism of immune escape mediated by the inhibition of lymphocyte proliferation and survival and by the induction of FoxP3+ T regulatory cells. Objective: To evaluate IDO1 expression in thyroid carcinoma and demonstrate its immunosuppressive function in the context of thyroid tumors. Setting: IDO1 expression was evaluated by QPCR in 105 papillary thyroid carcinomas (PTCs), 11 medullary thyroid carcinomas (MTCs), 6 anaplastic thyroid carcinomas (ATCs) and 5 thyroid carcinoma cell lines (TCCLs), by immunohistochemistry (IHC) in 55 PTCs and by western blotting in 5 TCCLs. FoxP3+ Treg lymphocyte density was evaluated by IHC in 29 PTCs. IDO1 inhibitory effect on lymphocyte proliferation was tested in co-culture experiments of TCCLs and activated lymphocytes. Results: IDO1 mRNA expression resulted significantly higher in all the analyzed thyroid carcinoma histotypes compared to normal thyroid. Interestingly, an increase of IDO1 mRNA expression magnitude could be observed with gain of aggressiveness (PTC & MTC ≪ ATC). In PTCs, IDO1 mRNA expression magnitude correlated with IDO1 immunostaining intensity in cancer cells and with FoxP3+ Treg lymphocyte density in the tumor microenvironment. IDO1 was expressed in human thyroid cancer cell lines in vitro and FTC133 cells showed high kynurenine concentration in the conditioned medium and a strong suppressive action on the proliferation of activated lymphocytes in co-culture experiments. Conclusions: For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.
INDOLEAMINE 2,3-DIOXYGENASE 1 (IDO1) IS UPREGULATED IN THYROID CARCINOMA AND DRIVES THE DEVELOPMENT OF AN IMMUNOSUPPRESSANT TUMOR MICROENVIRONMENT.
MORETTI, Sonia;MENICALI, ELISA;Voce P;MORELLI, SILVIA;FALLARINO, Francesca;ORABONA, Ciriana;ALUNNO, ALESSIA;BINI, Vittorio;GERLI, Roberto;PUCCETTI, Paolo;AVENIA, Nicola;PUXEDDU, Efisio
2014
Abstract
Context: Indoleamine 2,3-dioxygenase 1 (IDO1) is a single chain oxido-reductase that catalyzes tryptophan degradation to kynurenine. In cancer, it appears to exert an immunosuppressive function as part of an acquired mechanism of immune escape mediated by the inhibition of lymphocyte proliferation and survival and by the induction of FoxP3+ T regulatory cells. Objective: To evaluate IDO1 expression in thyroid carcinoma and demonstrate its immunosuppressive function in the context of thyroid tumors. Setting: IDO1 expression was evaluated by QPCR in 105 papillary thyroid carcinomas (PTCs), 11 medullary thyroid carcinomas (MTCs), 6 anaplastic thyroid carcinomas (ATCs) and 5 thyroid carcinoma cell lines (TCCLs), by immunohistochemistry (IHC) in 55 PTCs and by western blotting in 5 TCCLs. FoxP3+ Treg lymphocyte density was evaluated by IHC in 29 PTCs. IDO1 inhibitory effect on lymphocyte proliferation was tested in co-culture experiments of TCCLs and activated lymphocytes. Results: IDO1 mRNA expression resulted significantly higher in all the analyzed thyroid carcinoma histotypes compared to normal thyroid. Interestingly, an increase of IDO1 mRNA expression magnitude could be observed with gain of aggressiveness (PTC & MTC ≪ ATC). In PTCs, IDO1 mRNA expression magnitude correlated with IDO1 immunostaining intensity in cancer cells and with FoxP3+ Treg lymphocyte density in the tumor microenvironment. IDO1 was expressed in human thyroid cancer cell lines in vitro and FTC133 cells showed high kynurenine concentration in the conditioned medium and a strong suppressive action on the proliferation of activated lymphocytes in co-culture experiments. Conclusions: For the first time, this study demonstrates a pivotal role of IDO1 in the suppression of lymphocyte function in thyroid carcinoma microenvironment.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
