title: IL-15, TIM-3 and NK cells subsets predict responsiveness to anti-CTLA-4 treatment in melanoma patients.
abstract: Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3-CD56dimCD16+) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experimentsin vitrodemonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell linesin vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto , Catanzaro, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Tallerico
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto , Catanzaro, Italy.
authors.forename: Costanza M
authors.initials: CM
authors.lastname: Cristiani
authors.affiliation: Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet , Stockholm, Sweden.
authors.forename: Elina
authors.initials: E
authors.lastname: Staaf
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto , Catanzaro, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Garofalo
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto, Catanzaro, Italy; Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rosa
authors.initials: R
authors.lastname: Sottile
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Capone
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Yago
authors.initials: Y
authors.lastname: Pico de Coaña
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Madonna
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto , Catanzaro, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Palella
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Wolodarski
authors.affiliation: Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet , Stockholm, Sweden.
authors.forename: Valentina
authors.initials: V
authors.lastname: Carannante
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Mallardo
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Grimaldi
authors.affiliation: Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet , Stockholm, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Johansson
authors.affiliation: Karolinska Institutet Statistical Core Facility, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Paolo
authors.initials: P
authors.lastname: Frumento
authors.affiliation: Department of Health Sciences, University "Magna Græcia" of Catanzaro, Campus - Germaneto , Catanzaro, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Gulletta
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Department of Experimental Oncology and Molecular Medicine , Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
authors.affiliation: Department of Obstetrics and Gynecology, University of Cambridge Clinical School , Cambridge, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
authors.affiliation: Scientific Directorate, IRCCS Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Gennaro
authors.initials: G
authors.lastname: Ciliberto
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet , Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.affiliation: Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet , Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.affiliation: Melanoma Cancer Immunotherapy and Innovative Therapy Unit, Istituto Nazionale Tumori Fondazione "G. Pascale ," Napoli, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Tumor Immunology and Immunopathology Laboratory, Department of Experimental and Clinical Medicine, University "Magna Græcia" of Catanzaro, Campus - Germaneto, Catanzaro, Italy; Department of Microbiology, Cell and Tumorbiology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ennio
authors.initials: E
authors.lastname: Carbone
keywords: Anti-CTLA-4; IL-15; NK cells; PD-1; TIM-3; melanoma