HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism
Roberta Rizzo,
Valentina Audrito,
Paola Vacca,
Davide Rossi,
Davide Brusa,
Marina Stignani,
Daria Bortolotti,
Giovanni D’Arena,
Marta Coscia,
Luca Laurenti,
Francesco Forconi,
Gianluca Gaidano,
Maria Cristina Mingari,
Lorenzo Moretta,
Fabio Malavasi,
Silvia Deaglio
Affiliations
Roberta Rizzo
Department of Medical Sciences, Sections of Microbiology and Medical Genetics, University of Ferrara, Italy
Valentina Audrito
Department of Medical Sciences, University of Turin, Italy;Human Genetics Foundation (HuGeF), Turin, Italy
Paola Vacca
Department of Experimental Medicine, University of Genoa, Italy
Davide Rossi
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Davide Brusa
Human Genetics Foundation (HuGeF), Turin, Italy
Marina Stignani
Department of Medical Sciences, Sections of Microbiology and Medical Genetics, University of Ferrara, Italy
Daria Bortolotti
Department of Medical Sciences, Sections of Microbiology and Medical Genetics, University of Ferrara, Italy
Giovanni D’Arena
Department of Onco-Hematology, IRCCS “Centro di Riferimento Oncologico della Basilicata”, Rionero in Vulture, Italy
Marta Coscia
Division of Hematology, University of Turin, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Italy
Luca Laurenti
Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy
Francesco Forconi
Cancer Sciences Unit, CRUK Center, University of Southampton & Haematology Department, SUHT, Southampton, UK
Gianluca Gaidano
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Maria Cristina Mingari
Department of Experimental Medicine, University of Genoa, Italy;AOU San Martino–Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Lorenzo Moretta
Giannina Gaslini Institute, Genoa, Italy
Fabio Malavasi
Department of Medical Sciences, University of Turin, Italy;Research Center for Experimental Medicine, Città della Salute e della Scienza Hospital, Turin, Italy
Silvia Deaglio
Department of Medical Sciences, University of Turin, Italy;Human Genetics Foundation (HuGeF), Turin, Italy
This work investigates the possibility that HLA-G, a molecule modulating innate and adaptive immunity, is part of an immune escape strategy of chronic lymphocytic leukemia cells. A 14 base pair insertion/deletion polymorphism (rs66554220) in the 3′-untranslated region of HLA-G influences mRNA stability and protein expression. The analysis of a cohort of patients with chronic lymphocytic leukemia confirmed that del/del individuals are characterized by higher levels of surface and soluble HLA-G than subjects with the other two genotypes. In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions.
