Characterization of thein vivoimmune network of IDO, tryptophan metabolism, PD-L1, andCTLA-4in circulating immune cells in melanoma

Abstract

In melanoma, both the induction of immunosuppression by tumor cells and the inflammatory antitumor response can induce an upregulation of counter-regulatory mechanisms such as indoleamine 2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1) and CTLA-4 C regulatory T-cells (Tregs) in the tumor microenvironment. Even though these immunosuppressive mediators are targets for immunotherapy, research investigating their expression in the peripheral blood is lacking. We therefore, performed flow cytometry on PBMCs of stage I-IV melanoma patients. IDO expression was detected in plasmacytoid dendritic cells (pDC) and monocytic myeloid-derived suppressor cells (mMDSC), and increased in advanced disease stage (p D 0.027). Tryptophan breakdown confirmed the functional activity of IDO and was linked with increased PD-L1C cytotoxic T-cells (p D 0.009), relative lymphopenia (p D 0.036), and a higher mDC/pDC ratio (p D 0.002). High levels of circulating PD-L1C cytotoxic T-cells were associated with increased CTLA-4 expression by Tregs (p D 0.005) and MDSC levels (p D 0.033). This illustrates that counter-regulatory immune mechanisms in melanoma should be considered as one interrelated signaling network. Moreover, both increased PD-L1C T-cells and CTLA-4 expression in Tregs conferred a negative prognosis, indicating their in vivo relevance. Remarkably, circulating CTLA-4, IDO, and pDC levels were altered according to prior invasion of the sentinel lymph node and IDO expression in the sentinel was associated with more IDOC PBMCs. We conclude that the expression of IDO, PD-L1, and CTLA-4 in the peripheral blood of melanoma patients is strongly interconnected, associated with advanced disease and negative outcome, independent of disease stage. Combination treatments targeting several of these markers are therefore likely to exert a synergistic response.

Early Immune Regulatory Changes in a Primary Controlled Human Plasmodium vivax Infection: CD1c + Myeloid Dendritic Cell Maturation Arrest, Induction of the Kynurenine Pathway, and Regulatory T Cell Activation

“…Modulation of microenvironment tryptophan availability through increased IDO activity is a well-characterized mechanism of immune regulation by tolerogenic DC (19). While IDO activity has been demonstrated for human pDC (45)(46)(47) and CD1c ϩ mDC (48), we did not measure DC-specific IDO expression in this study, and the observed drastic increase in the plasma KT ratio is unlikely to be attributable to DC alone. Mouse models of malaria have …”

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

“…In line with our results, a recent study showed that exhausted T cells are associated with increased CTLA-4 expression in MDSCs in melanoma. 34 However, it remained unclear whether CTLA-4 inhibits tumor growth in a MDSCs and M2 macrophage dependent manner. In our mouse model, we observed that blockade of CTLA4 reduced the number of MDSCs and M2 macrophages in the tumor and the immune organ.…”

Myeloid-Derived Suppressor Cells in Some Oncohematological Diseases

“…В основном супрессорное влияние IDO на T-клетки связывают с истощением незаме-нимой аминокислоты триптофана, при отсутствии которой наблюдается остановка клеточного цикла [28,29]. В последнее время имеются предположения, что механизм IDO более сложен и супрессивными свойствами обладают метаболиты триптофана.…”