title: A CCR4 antagonist combined with vaccines induces antigen-specific CD8+ T cells and tumor immunity against self antigens.
abstract: Regulatory T cells (Tregs) may impede cancer vaccine efficacy in hematologic malignancies and cancer. CCR4 antagonists, an emergent class of Treg inhibitor, have been shown to block recruitment of Tregs mediated by CCL22 and CCL17. Our aim was to demonstrate the ability of a CCR4 antagonist (a small chemical molecule identified in silico) when combined with vaccines to break peripheral tolerance controlled by Tregs, a prerequisite for the induction of CD8(+) T cells against self Ags. Immunization of transgenic or normal mice expressing tumor-associated self Ags (Her2/neu, OVA, gp100) with a CCR4 antagonist combined with various vaccines led to the induction of effector CD8(+) T cells and partial inhibition of tumor growth expressing self Ags in both prophylactic and therapeutic settings. The CCR4 antagonist was more efficient than cyclophosphamide to elicit anti-self CD8(+) T cells. We also showed that the population of Tregs expressing CCR4 corresponded to memory (CD44(high)) and activated (ICOS(+)) Tregs, an important population to be targeted to modulate Treg activity. CCR4 antagonist represents a competitive class of Treg inhibitor able to induce functional anti-self CD8(+) T cells and tumor growth inhibition when combined with vaccines. High expression of CCR4 on human Tregs also supports the clinical development of this strategy.
authors: Inserm U970 PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Paris, France.
authors: Helene
authors: H
authors: Pere
authors: Yves
authors: Y
authors: Montier
authors: Jagadeesh
authors: J
authors: Bayry
authors: Francoise
authors: F
authors: Quintin-Colonna
authors: Nathalie
authors: N
authors: Merillon
authors: Estelle
authors: E
authors: Dransart
authors: Cecile
authors: C
authors: Badoual
authors: Alain
authors: A
authors: Gey
authors: Patrice
authors: P
authors: Ravel
authors: Elie
authors: E
authors: Marcheteau
authors: Frederic
authors: F
authors: Batteux
authors: Federico
authors: F
authors: Sandoval
authors: Olivier
authors: O
authors: Adotevi
authors: Christopher
authors: C
authors: Chiu
authors: Sylvie
authors: S
authors: Garcia
authors: Corinne
authors: C
authors: Tanchot
authors: Yu-Chun
authors: YC
authors: Lone
authors: Luis Carlos
authors: LC
authors: Ferreira
authors: Brad H
authors: BH
authors: Nelson
authors: Douglas
authors: D
authors: Hanahan
authors: Wolf Herman
authors: WH
authors: Fridman
authors: Ludger
authors: L
authors: Johannes
authors: Eric
authors: E
authors: Tartour
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001324:Autoantigens / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors*; D037182:T-Cell Antigen Receptor Specificity / Q000187:drug effects / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects* / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001324:Autoantigens; D019496:Cancer Vaccines; C515355:Ccr4 protein, mouse; D007155:Immunologic Factors; D054398:Receptors, CCR4