title: Multiple Myeloma Impairs Bone Marrow Localization of Effector Natural Killer Cells by Altering the Chemokine Microenvironment.
abstract: Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ponzetta
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Benigni
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Antonangeli
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sciumè
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Sanseviero
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Ricciardi
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Petrucci
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. IRCCS, Neuromed, Pozzilli, IS, Italy. angela.santoni@uniroma1.it giovanni.bernardini@uniroma1.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: Department of Molecular Medicine-Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. IRCCS, Neuromed, Pozzilli, IS, Italy. angela.santoni@uniroma1.it giovanni.bernardini@uniroma1.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bernardini
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D018925:Chemokines / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D018925:Chemokines