title: Regulation of CD4(+)NKG2D(+) Th1 cells in patients with metastatic melanoma treated with sorafenib: role of IL-15Rα and NKG2D triggering.
abstract: Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4(+)NKG2D(+) T cells. Hence, the increase of blood CD4(+)NKG2D(+) T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4(+)NKG2D(+) subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D(+) Th1 cells.
authors.affiliation: Authors' Affiliations: Cancer Institute Gustave Roussy; Departments of Epidemiology and Statistics and Dermatology; Stabilité génétique et oncogenèse UMR 8200; Clinical Oncology, Melanoma Branch, Cancer Institute Gustave Roussy; Department of BioPathology, Translational Research Laboratory and Biobank, Institute Gustave Roussy; Institut National de la Santé et de la Recherche Medicale (INSERM), U1015; Center of Clinical Investigations CBT507, Biotherapy, Villejuif; INSERM U1102, Institut de Cancérologie de l'Ouest, Saint Herblain; INSERM, U892, Institut de Recherche Thérapeutique, Nantes; INSERM, U1016, Saint Vincent de Paul Hospital; INSERM U1016, CNRS UMR8104, Cochin Institute; Faculté Paris Sud-Université Paris XI, Paris, France; and IRCCS San Matteo University Hospital Foundation, Pavia, Italy.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Romero
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.forename: Vichnou
authors.initials: V
authors.lastname: Poirier-Colame
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacquelot
authors.forename: Kariman
authors.initials: K
authors.lastname: Chaba
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.forename: Sophie
authors.initials: S
authors.lastname: Caillat-Zucman
authors.forename: Caroline
authors.initials: C
authors.lastname: Flament
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
authors.forename: Meriem
authors.initials: M
authors.lastname: Messaoudene
authors.forename: Anne
authors.initials: A
authors.lastname: Aupérin
authors.forename: Philippe
authors.initials: P
authors.lastname: Vielh
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.forename: Maha
authors.initials: M
authors.lastname: Ayyoub
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000276:immunology; D048708:Cell Growth Processes / Q000276:immunology; D005260:Female; D006801:Humans; D019409:Interleukin-15 / Q000276:immunology; D053720:Interleukin-15 Receptor alpha Subunit / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D000077157:Sorafenib; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D055655:NK Cell Lectin-Like Receptor Subfamily K; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib