IDO1 Inhibition Overcomes Radiation-Induced “Rebound Immune Suppression” by Reducing Numbers of IDO1-Expressing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment
Menée à l'aide d'un modèle murin de carcinome pulmonaire de Lewis, cette étude montre que l'inhibition de l'indoléamine 2, 3-dioxygénase (IDO1) lève la suppression immunitaire liée aux rayonnements ionisants en réduisant, dans le micro-environnement tumoral, le nombre de cellules myéloïdes suppressives exprimant IDO1
Purpose : The limitation of hypofractionated radiation efficacy is due partly to the immunosuppressive tumor microenvironment. Indoleamine-2,3-dioxygenase 1 (IDO1) is an important regulator of tumor immune suppression. We evaluated the effects of IDO1 in hypofractionated radiation using a Lewis lung carcinoma (LLC) mouse model and tested whether IDO1 inhibition could sensitize those tumors to hypofractionated radiation. Methods and Materials : Bilateral LLC tumors were established in C57BL/6 mice. Primary tumors were treated with 3 fractions of either 12-Gy or 6-Gy, and the IDO1 inhibitor INCB023843 was given starting on the first day of radiation. Plasma tryptophan (Trp) and kynurenine (Kyn) levels were quantified by liquid chromatography/tandem mass spectrometry. Tumor-infiltrating immune cells were isolated from the tumors, stained, and quantified by flow cytometry. Results : The combination of INCB023843 and three 12-Gy fractions led to better tumor control and survival than radiation alone; INCB023843 plus three 6-Gy fractions had no benefit. IDO1 expression by tumor-infiltrating immune cells were increased by three 12-Gy doses and inhibited by the addition of INCB023843. Nearly all IDO1+ immune cells were also F4/80+. Percentages of IDO1+F4/80+ immune cells were drastically increased by three 12-Gy fractions and also by three 6-Gy fractions, but only INCB023843 combined with three 12-Gy fractions reduced those percentages. IDO1+F4/80+ immune cells were further found to be CD11b+, Gr1-intermediate-expressing, CD206–, and CD11c–, i.e., myeloid-derived suppressor cells (MDSCs). Three 12-Gy fractions also increased the percentages of tumor-infiltrating T regulatory cells and CD8+ T cells but adding INCB023843 did not affect those percentages. Conclusions : In addition to its immune activation effects, hypofractionated radiation induced “rebound immune suppression” in the tumor microenvironment by activating and recruiting IDO1-expressing MDSCs in a dose-dependent manner. Adding an IDO1 inhibitor to hypofractionated radiation reduced the percentages of these cells, overcame the immune suppression, and sensitized LLC tumors to hypofractionated radiation.