Human anaplastic thyroid carcinoma cells are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract NK cells.

Abstract

PURPOSE:

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive forms of cancer with no curative therapies available. To date, strategies to target ATC by immunotherapy have not been evaluated. We investigated whether ATC would be a suitable target for natural killer (NK) cell-based immunotherapy.

EXPERIMENTAL DESIGN:

We first established seven new cell lines from ATC tumors, three from papillary thyroid carcinoma tumors and analyzed them together with eight additional ATC cell lines. Cells were analyzed for sensitivity to lysis by NK cells and their ability to chemoattract and regulate the activity of NK cells. In addition, fresh tumor samples and peripheral blood from six patients with ATC were analyzed for NK cell infiltration and phenotype.

RESULTS:

We observed that ATC cell lines are sensitive to lysis by ex vivo expanded NK cells and that the lysis was abrogated upon blockade of NKG2D. Sensitivity of thyroid cancer cell lines to NK cell-mediated lysis correlated with surface expression of UL16-binding protein 2 on tumor cells. Moreover, ATC cell lines produced high levels of CXCL10 and stimulated migration of expanded NK cells and ATC tumors were enriched for NK cells expressing the cognate chemokine receptor CXCR3. However, compared with NK cells in peripheral blood, ATC tumor-derived NK cells displayed a suppressed phenotype with a downregulated expression of NKG2D. In vitro, suppression of NK cell-mediated lysis and NKG2D expression by ATC cells was restored upon neutralization of prostaglandin-E2.

CONCLUSIONS:

ATC cell lines are sensitive to NK cell-mediated lysis via ULBP2/5/6 and chemoattract CXCR3-positive NK cells. Patients with ATC may benefit from NK cell-based immunotherapy.

• Authors: Erik Wennerberg, Aline Pfefferle, Lars Ekblad, Yuya Yoshimoto, Veronika Kremer, Vitaliy O Kaminskyy, C Christofer Juhlin, Anders Höög, Inger Bodin, Vitalijs Svjatoha, Catharina Larsson, Jan Zedenius, Johan Wennerberg, Andreas Lundqvist
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 20 Issue 22 Pg. 5733-44 (Nov 15 2014) ISSN: 1557-3265 [Electronic] United States
• PMID: 25212604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Blocking
• Antibodies, Monoclonal
• Chemokine CXCL10
• GPI-Linked Proteins
• Intercellular Signaling Peptides and Proteins
• NK Cell Lectin-Like Receptor Subfamily K
• Receptors, CXCR3
• TNF-Related Apoptosis-Inducing Ligand
• ULBP2 protein, human
• Cyclooxygenase 2
• Dinoprostone

Topics

• Antibodies, Blocking (pharmacology)
• Antibodies, Monoclonal (pharmacology)
• Cell Line, Tumor
• Chemokine CXCL10 (biosynthesis)
• Chemotaxis (immunology)
• Cyclooxygenase 2 (genetics, metabolism)
• Cytotoxicity, Immunologic (drug effects)
• Dinoprostone (metabolism)
• GPI-Linked Proteins (genetics, metabolism)
• Gene Expression
• Humans
• Immunophenotyping
• Intercellular Signaling Peptides and Proteins (genetics, metabolism)
• Killer Cells, Natural (immunology, metabolism)
• NK Cell Lectin-Like Receptor Subfamily K (antagonists & inhibitors, metabolism)
• Phenotype
• Receptors, CXCR3 (genetics, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (antagonists & inhibitors, metabolism)
• Thyroid Carcinoma, Anaplastic (genetics, immunology, metabolism)