title: Natural Killer (NK)/melanoma cell interaction induces NK-mediated release of chemotactic High Mobility Group Box-1 (HMGB1) capable of amplifying NK cell recruitment.
abstract: In this study we characterize a new mechanism by which Natural Killer (NK) cells may amplify their recruitment to tumors. We show that NK cells, upon interaction with melanoma cells, can release a chemotactic form of High Mobility Group Box-1 (HMGB1) protein capable of attracting additional activated NK cells. We first demonstrate that the engagement of different activating NK cell receptors, including those mainly involved in tumor cell recognition can induce the active release of HMGB1. Then we show that during NK-mediated tumor cell killing two HMGB1 forms are released, each displaying a specific electrophoretic mobility possibly corresponding to a different redox status. By the comparison of normal and perforin-defective NK cells (which are unable to kill target cells) we demonstrate that, in NK/melanoma cell co-cultures, NK cells specifically release an HMGB1 form that acts as chemoattractant, while dying tumor cells passively release a non-chemotactic HMGB1. Finally, we show that Receptor for Advanced Glycation End products is expressed by NK cells and mediates HMGB1-induced NK cell chemotaxis. Proteomic analysis of NK cells exposed to recombinant HMGB1 revealed that this molecule, besides inducing immediate chemotaxis, also promotes changes in the expression of proteins involved in the regulation of the cytoskeletal network. Importantly, these modifications could be associated with an increased motility of NK cells. Thus, our findings allow the definition of a previously unidentified mechanism used by NK cells to amplify their response to tumors, and provide additional clues for the emerging role of HMGB1 in immunomodulation and tumor immunity.
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Parodi
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pedrazzi
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; Center of Excellence for Biomedical Research (CEBR); University of Genova ; Genova, Italy ; Istituto Giannina Gaslini ; Genova, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cantoni
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; Center of Excellence for Biomedical Research (CEBR); University of Genova ; Genova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Averna
authors.affiliation: Department of Sciences and Technological Innovation (DiSIT); University of Piemonte Orientale ; Alessandria, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Patrone
authors.affiliation: Department of Sciences and Technological Innovation (DiSIT); University of Piemonte Orientale ; Alessandria, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cavaletto
authors.affiliation: Department of Sciences and Technological Innovation (DiSIT); University of Piemonte Orientale ; Alessandria, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Spertino
authors.affiliation: IRCCS AOU San Martino-IST ; Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy.
authors.forename: Mirna
authors.initials: M
authors.lastname: Balsamo
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; IRCCS AOU San Martino-IST ; Genova, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pietra
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; Center of Excellence for Biomedical Research (CEBR); University of Genova ; Genova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Sivori
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Carlomagno
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; Center of Excellence for Biomedical Research (CEBR); University of Genova ; Genova, Italy ; IRCCS AOU San Martino-IST ; Genova, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Mingari
authors.affiliation: Istituto Giannina Gaslini ; Genova, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Department of Experimental Medicine (DIMES); University of Genova ; Genova, Italy ; Center of Excellence for Biomedical Research (CEBR); University of Genova ; Genova, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Sparatore
authors.affiliation: IRCCS AOU San Martino-IST ; Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Vitale
keywords: HMGB1; NK cells; chemotaxis; melanoma cells; tumor microenvironment