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161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS
Univ Minnesota, Mason Canc Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.ORCID-id: 0000-0003-2040-3176
Univ Minnesota, Mason Canc Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
KTH, Centra, Science for Life Laboratory, SciLifeLab. KTH, Skolan för teknikvetenskap (SCI), Tillämpad fysik.ORCID-id: 0000-0003-1016-2460
Vise andre og tillknytning
2018 (engelsk)Inngår i: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, nr 12, s. 1459-1469Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 x CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)-treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE-treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE-treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients.

sted, utgiver, år, opplag, sider
AMER SOC HEMATOLOGY , 2018. Vol. 2, nr 12, s. 1459-1469
HSV kategori
Identifikatorer
URN: urn:nbn:se:kth:diva-232250DOI: 10.1182/bloodadvances.2017012369ISI: 000436548300013PubMedID: 29941459Scopus ID: 2-s2.0-85060540460OAI: oai:DiVA.org:kth-232250DiVA, id: diva2:1233960
Forskningsfinansiär
Swedish Foundation for Strategic Research , SBE13-0092Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Merknad

QC 20180720

Tilgjengelig fra: 2018-07-20 Laget: 2018-07-20 Sist oppdatert: 2019-08-20bibliografisk kontrollert

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Brandt, LudwigGuldevall, KarolinÖnfelt, Björn

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