Neutrophil extracellular traps arm DC vaccination against NPM-mutant myeloproliferation

eLife

Paolo Verderio¹  Mara Lecchi¹  Patrizia Comoli²  Antonio Curti³  Cesare Valenti⁴  Sabina Sangaletti⁵  Paola Portararo⁵  Barbara Bassani⁵  Milena Perrone⁵  Mario P Colombo⁵  Elena Jachetti⁵  Laura Botti⁵  Claudia Chiodoni⁵  Maurilio Ponzoni⁶  Claudio Tripodo⁷  Valeria Cancila⁷ 

[1] Bioinformatics and Biostatistics Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy;Cell Factory, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;Department of Experimental, Diagnostic and Specialty Medicine – DIMES, Institute of Hematology "Seràgnoli", Bologna, Italy;Department of Mathematics and Informatics, University of Palermo, Palermo, Italy;Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy;Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy;Tumor Immunology Unit, Department of Health Sciences, University of Palermo, Palermo, Italy;

关键词: vaccine;    extracellular traps;    nucleophosmin;    myeloproliferation;   

DOI  :  10.7554/eLife.69257

来源: DOAJ

【 摘 要 】

Neutrophil extracellular traps (NETs) are web-like chromatin structures composed by dsDNA and histones, decorated with antimicrobial proteins. Their interaction with dendritic cells (DCs) allows DC activation and maturation toward presentation of NET-associated antigens. Differently from other types of cell death that imply protein denaturation, NETosis preserves the proteins localized onto the DNA threads for proper enzymatic activity and conformational status, including immunogenic epitopes. Besides neutrophils, leukemic cells can release extracellular traps displaying leukemia-associated antigens, prototypically mutant nucleophosmin (NPMc+) that upon mutation translocates from nucleolus to the cytoplasm localizing onto NET threads. We tested NPMc+ immunogenicity through a NET/DC vaccine to treat NPMc-driven myeloproliferation in transgenic and transplantable models. Vaccination with DC loaded with NPMc+ NET (NPMc+ NET/DC) reduced myeloproliferation in transgenic mice, favoring the development of antibodies to mutant NPMc and the induction of a CD8+ T-cell response. The efficacy of this vaccine was also tested in mixed NPMc/WT bone marrow (BM) chimeras in a competitive BM transplantation setting, where the NPMc+ NET/DC vaccination impaired the expansion of NPMc+ in favor of WT myeloid compartment. NPMc+ NET/DC vaccination also achieved control of an aggressive leukemia transduced with mutant NPMc, effectively inducing an antileukemia CD8 T-cell memory response.

【 授权许可】

Unknown