title: Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients.
abstract: Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dimand CD16+NK cells, and a higher frequency of GrzB+cells in CD56dim, CD56bright, and CD16+NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon γ (IFNγ) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower "natural" cytotoxicity. A marked and prolonged therapy-induced reduction of both "natural" and CD16-dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dimsubset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNγ production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies.
authors.affiliation: Hematology Unit; Sant'Andrea Hospital; Sapienza University ; Rome, Italy.
authors.forename: M Christina
authors.initials: MC
authors.lastname: Cox
authors.affiliation: Department of Experimental Medicine; Sapienza University ; Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Battella
authors.affiliation: Department of Experimental Medicine; Sapienza University ; Rome, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: La Scaleia
authors.affiliation: Hematology Unit; Sant'Andrea Hospital; Sapienza University ; Rome, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pelliccia
authors.affiliation: Department of Clinical and Molecular Medicine; Sapienza University ; Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Di Napoli
authors.affiliation: Department of Molecular Medicine; Sapienza University ; Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Porzia
authors.affiliation: Department of Molecular Medicine; Sapienza University ; Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cecere
authors.affiliation: Hematology Unit; Sant'Andrea Hospital; Sapienza University ; Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Alma
authors.affiliation: Department of Molecular Medicine; Sapienza University ; Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Zingoni
authors.affiliation: Department of Experimental Medicine; Sapienza University ; Rome, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mainiero
authors.affiliation: Department of Clinical and Molecular Medicine; Sapienza University ; Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ruco
authors.affiliation: Hematology Unit; Sant'Andrea Hospital; Sapienza University ; Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Monarca
authors.affiliation: Department of Molecular Medicine; Sapienza University ; Rome, Italy ; Istituto Pasteur-Fondazione Cenci Bolognetti; Sapienza University ; Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Santoni
authors.affiliation: Department of Experimental Medicine; Sapienza University ; Rome, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Palmieri
keywords: ADCC; ADCC, antibody-dependent cellular cytotoxicity; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; FcγRIIIA/CD16, type III low-affinity Fcγ receptor; GrzB, Granzyme B; IFNγ, interferon γ; NK, natural killer cells; PBMC, peripheral blood mononuclear cell; PMLBCL, primary mediastinal large B-cell lymphoma; R-CHOP, rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone.; CD16; DLBCL; NK cells; NKG2D; R-CHOP immunochemotherapy; rituximab