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Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA..
Nova Southeastern Univ, Dr Kiran C Patel Coll Allopath Med, Ft Lauderdale, FL 33314 USA.;Nova Southeastern Univ, NSU Cell Therapy Inst, Ft Lauderdale, FL 33314 USA.;Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
Karolinska Univ Hosp Huddinge, Karolinska Inst, Ctr Hematol & Regenerat Med, Stockholm, Sweden..
Sabanci Univ, Fac Engn & Nat Sci, Istanbul, Turkey..
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2020 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 11, article id 40Article in journal (Refereed) Published
Abstract [en]

Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA , 2020. Vol. 11, article id 40
Keywords [en]
cancer immunotherapy, cancer immunology, sarcoma, natural killer (NK) cell, DNAM-1 (CD226), NKG2D (Natural killer group 2 member D), NK-92 cell line
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-269481DOI: 10.3389/fimmu.2020.00040ISI: 000514603100001PubMedID: 32082316Scopus ID: 2-s2.0-85079487408OAI: oai:DiVA.org:kth-269481DiVA, id: diva2:1413022
Note

QC 20200309

Available from: 2020-03-09 Created: 2020-03-09 Last updated: 2020-03-09Bibliographically approved

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Arif, MuhammadMardinoglu, Adil

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