title: Systemic immune changes associated with adjuvant interferon-α2b-therapy in stage III melanoma patients: failure at the effector phase?
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.
authors.affiliation: Departments of aDermatology bMedical Oncology, Ghent University Hospital, Ghent cDepartment of Medical Oncology, UZ-Brussel, Brussels, Belgium dToxicology Laboratory, CHU Lille, Lille, France.
authors.forename: Ines
authors.initials: I
authors.lastname: Chevolet
authors.forename: Max
authors.initials: M
authors.lastname: Schreuer
authors.forename: Reinhart
authors.initials: R
authors.lastname: Speeckaert
authors.forename: Bart
authors.initials: B
authors.lastname: Neyns
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hoorens
authors.forename: Nanja
authors.initials: N
authors.lastname: van Geel
authors.forename: Vibeke
authors.initials: V
authors.lastname: Krüse
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hennart
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Mireille
authors.initials: M
authors.lastname: Van Gele
authors.forename: Lieve
authors.initials: L
authors.lastname: Brochez
mesh_terms: D000328:Adult; D000368:Aged; D060890:B7-H1 Antigen / Q000096:biosynthesis; D060908:CTLA-4 Antigen / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D005060:Europe; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D016898:Interferon-alpha / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D022423:Myeloid Cells / Q000276:immunology*; D009367:Neoplasm Staging; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000096142:Cutaneous Malignant Melanoma
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha