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Here we extend our previous observation that, in human NK cells, the sustained CD16 ligation by obinutuzumab-opsonized targets leads to a markedly enhanced IFN-\u03b3 production upon a subsequent cytokine re-stimulation. The increased IFN-\u03b3 competence in response to IL-2 or IL-15 is attributable to post-transcriptional regulation, as it does not correlate with the upregulation of IFN-\u03b3 mRNA levels. Different from the reference molecule rituximab, we observe that the stimulation with obinutuzumab promotes the upregulation of microRNA (miR)-155 expression. A similar trend was also observed in NK cells from untreated CLL patients stimulated with obinutuzumab-opsonized autologous leukemia. miR-155 upregulation associates with reduced levels of SHIP-1 inositol phosphatase, which acts in constraining PI3K-dependent signals, by virtue of its ability to mediate phosphatidylinositol 3,4,5-trisphosphate (PIP3) de-phosphorylation. Downstream of PI3K, the phosphorylation status of mammalian target of rapamycin (mTOR) effector molecule, S6, results in amplified response to IL-2 or IL-15 stimulation in obinutuzumab-experienced cells. Importantly, NK cell treatment with the PI3K or mTOR inhibitors, idelalisib and rapamycin, respectively, prevents the enhanced cytokine responsiveness, thus, highlighting the relevance of the PI3K\/mTOR axis in CD16-dependent priming. The enhanced IFN-\u03b3 competence may be envisaged to potentiate the immunoregulatory role of NK cells in a therapeutic setting.<\/jats:p>","DOI":"10.1007\/s00262-020-02482-2","type":"journal-article","created":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T11:27:45Z","timestamp":1579174065000},"page":"501-512","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["CD16 pre-ligation by defucosylated tumor-targeting mAb sensitizes human NK cells to \u03b3c cytokine stimulation via PI3K\/mTOR axis"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6747-3836","authenticated-orcid":false,"given":"Cristina","family":"Capuano","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6163-0135","authenticated-orcid":false,"given":"Chiara","family":"Pighi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8319-4418","authenticated-orcid":false,"given":"Roberta","family":"Maggio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1882-1451","authenticated-orcid":false,"given":"Simone","family":"Battella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2441-9749","authenticated-orcid":false,"given":"Stefania","family":"Morrone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1467-1417","authenticated-orcid":false,"given":"Gabriella","family":"Palmieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1206-7731","authenticated-orcid":false,"given":"Angela","family":"Santoni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Klein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2660-1456","authenticated-orcid":false,"given":"Ricciarda","family":"Galandrini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"2482_CR1","unstructured":"Pighi C, Capuano C, Maggio R et al (2019) CD16 aggregation in high affinity conditions by tumor-targeting mAb obinutuzumab promotes a PI3K\/mTOR-dependent priming of Natural Killer cells for IFN-gamma production, associated to miR-155 upregulation. 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All other authors declare that they have no conflict of interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"All procedures involving human participants were in accordance with the ethical standards of the institutional research committee and with 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of Sapienza University of Rome (approval number 639\/16 RIF\/CE 4179).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and ethical standards"}},{"value":"All experiments were performed after obtaining written informed consent from patients and healthy donors. The informed consent was taken at the beginning of the study to use data and materials for research and publication of this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}},{"value":"RPMI 8866 cell line was purchased by American Type Culture Collection, and Raji cell line was provided by Dr. F.D. Batista. Cells were authenticated (last testing May 2019) by morphology, growth and immunophenotypic characteristics, biologic behavior according to the provider recommendations, and routinely tested for mycoplasma contamination by EZ-PCR Mycoplasma test kit (#20\u2013700-20, Biological Industries). All cell lines were kept in culture for less than two consecutive months.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Cell line authentication"}}]}}