title: Polyfunctional Melan-A-specific tumor-reactive CD8(+) T cells elicited by dacarbazine treatment before peptide-vaccination depends on AKT activation sustained by ICOS.
abstract: The identification of activation pathways linked to antitumor T-cell polyfunctionality in long surviving patients is of great relevance in the new era of immunotherapy. We have recently reported that dacarbazine (DTIC) injected one day before peptide-vaccination plus IFN-α improves the antitumor lytic activity and enlarges the repertoire of Melan-A-specific T-cell clones, as compared with vaccination alone, impacting the overall survival of melanoma patients. To identify the mechanisms responsible for this improvement of the immune response, we have analyzed the endogenous and treatment-induced antigen (Ag)-specific response in a panel of Melan-A-specific CD8(+) T-cell clones in terms of differentiation phenotype, inhibitory receptor profile, polyfunctionality and AKT activation. Here, we show that Melan-A-specific CD8(+) T cells isolated from patients treated with chemoimmunotherapy possess a late differentiated phenotype as defined by the absence of CD28 and CD27 co-stimulatory molecules and high levels of LAG-3, TIM-3 and PD-1 inhibitory receptors. Nevertheless, they show higher proliferative potential and an improved antitumor polyfunctional effector profile in terms of co-production of TNF-α, IFNγ and Granzyme-B (GrB) compared with cells derived from patients treated with vaccination alone. Polyfunctionality is dependent on an active AKT signaling related to the engagement of the co-stimulatory molecule ICOS. We suggest that this phenotypic and functional signature is dictated by a fine-tuned balance between TCR triggering, AKT activation, co-stimulatory and inhibitory signals induced by chemoimmunotherapy and may be associated with antitumor T cells able to protect patients from tumor recurrence.
authors.affiliation: Department of Systems Medicine, University of Tor Vergata , Rome, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Franzese
authors.affiliation: Department of Molecular Medicine, University of Rome "La Sapienza;" Rome, Italy; Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Belinda
authors.initials: B
authors.lastname: Palermo
authors.affiliation: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Cosmo
authors.initials: C
authors.lastname: Di Donna
authors.affiliation: Biostatistics and Scientific Direction, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.affiliation: Department of Experimental Oncology, Medical Oncology 1, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferraresi
authors.affiliation: Department of Molecular Medicine, University of Rome "La Sapienza ;" Rome, Italy.
authors.forename: Helena
authors.initials: H
authors.lastname: Stabile
authors.affiliation: Department of Molecular Medicine, University of Rome "La Sapienza ;" Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Gismondi
authors.affiliation: Department of Molecular Medicine, University of Rome "La Sapienza ;" Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute , Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nisticò
keywords: AKT; CD8+ T cells; ICOS; Melan-A; chemoimmunotherapy; dacarbazine; human melanoma; polyfunctional