Systemic immune changes associated with adjuvant interferon-α2b-therapy in stage III melanoma patients: failure at the effector phase?. Issue 4 (August 2015)

• Record Type: Journal Article
• Authors: Chevolet, Ines; Schreuer, Max; Speeckaert, Reinhart; Neyns, Bart; Hoorens, Isabelle; van Geel, Nanja; Krüse, Vibeke; Hennart, Benjamin; Allorge, Delphine; Van Gele, Mireille; Brochez, Lieve
• Is Part Of: Melanoma research. Volume 25:Issue 4(2015)
• Publication Date: 2015-08
• Subjects: adjuvant interferon-α -- indoleamine 2, 3-dioxygenase -- melanoma -- negative feedback mechanism -- programmed-death ligand-1; Melanoma -- Periodicals; Melanoma -- Periodicals; Melanomen; 616.99477
• DOI: 10.1097/CMR.0000000000000171
• Languages: English
• ISSNs: 0960-8931

Abstract

Abstract : Interferon-α (IFN-α) is the only approved adjuvant treatment for high-risk melanoma patients in Europe, but the impact on overall survival is low. Although it is believed that IFN-α exerts its effects through immunomodulation, data on its impact on circulating immune cells are scarce. Flow cytometry was performed on peripheral blood mononuclear cells of eight IFN-α2b-treated stage III melanoma patients and 26 untreated stage III melanoma patients as controls to enumerate myeloid and plasmacytoid dendritic cells (mDC and pDC), monocytic and polymorphonuclear myeloid-derived suppressor cells (mMDSC and pmnMDSC) and cytotoxic and regulatory T-cells (Tregs). The expression of several immunosuppressive markers [indoleamine 2, 3-dioxygenase (IDO), programmed-death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA4)] was explored. IDO activity in the blood was confirmed by ultra-performance liquid chromatography. Compared with controls, IFN-α2b treatment was associated with increased IDO expression by pDCs ( P =0.021) and an increased kynurenine/tryptophan ratio in the serum ( P =0.004), compatible with IDO enzyme activity. Furthermore, IFN-α2b-treated patients had a decreased mDC/DC ratio ( P =0.002), decreased CD3+ lymphocytes ( P =0.034) and increased circulating Treg ( P <0.001) and PD-L1+cytotoxic T-cell ( P =0.001) frequencies. IDO expression is upregulated in circulating pDCs of high-risk melanoma patients treated with adjuvant IFN-α2b. This is associated with tryptophan consumption in the patients' serum and higher Treg and PD-L1+cytotoxic T-cell frequencies. We hypothesize that in IFN-α2b-treated patients, IDO activity acts as a negative feedback mechanism and might limit the clinical efficacy of IFN-α2b therapy. The underlying mechanism should be explored as this could lead to more efficient immunotherapies.