Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

• Published in: Oncoimmunology 2015-03, Vol.4 (3), p.e990773-e990773
• Main Authors: Cox, M Christina, Battella, Simone, La Scaleia, Raffaella, Pelliccia, Sabrina, Di Napoli, Arianna, Porzia, Alessandra, Cecere, Francesca, Alma, Eleonora, Zingoni, Alessandra, Mainiero, Fabrizio, Ruco, Luigi, Monarca, Bruno, Santoni, Angela, Palmieri, Gabriella
• Format: Article
• Language: English
• Subjects: 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; Original Research; R-CHOP immunochemotherapy; rituximab
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.4161/2162402X.2014.990773

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 CD56 dim and CD16 + NK cells, and a higher frequency of GrzB + cells in CD56 dim , CD56 bright , 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 CD56 dim subset. 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.