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. Clin Cancer Res; 20(22); 5733-44. Ó2014 AACR.

The immune network in thyroid cancer

“…PGE 2 was identified as the main candidate responsible for ATC-mediated NK cell suppression. 95 This study indicates that ATC could be a target for NK cell-based adoptive cell therapy, paving the way to novel immune-mediated therapeutic approach to ATC.…”

“…94 From the functional point of view, ATC cell lines were sensitive to lysis by PBMC-derived NK cells. 95 NK cell-mediated lysis of ATC was dependent on the expression of the activating receptor NKG2D on NK cells and its ligands ULBP2/5/6 on ATC cells. Indeed, ATC cell lines and TC derived from human fine-needle aspiration (FNA) samples from ATC patients expressed ULB2/5/6, whereas non-malignant thyroid tissue did not.…”

IL-12 immunotherapy of Braf-induced papillary thyroid cancer in a mouse model

“…The therapeutic effects of both IL-12 gene therapy and recombinant protein therapy are comparable and are mediated via CD8 + T and NK cells. Wennerberg et al 28 have recently demonstrated that human anaplastic thyroid carcinoma (ATC) cells are also sensitive to NK cell-mediated lysis and ATC-derived NK cells display a suppressed phenotype with downregulated expression of NKG2D, which is an activating receptor expressed on CD8 + T and NK cells. 29 They further demonstrate that the suppression of NK cell-mediated lysis can be restored by blocking prostaglandin-E2, indicating Cox-2 inhibitors may have therapeutic benefit against ATC.…”

Immune responses in the thyroid cancer microenvironment: making immunotherapy a possible mission

“…NK cells differentiate their targets from 'healthy self' by integrating signals from multiple inhibitory and activating receptors. Nevertheless, few solid tumors have shown to be responsive to NK cell-mediated immunotherapy due to resistance to NK cell-induced lysis, as well as poor homing and infiltration of NK cells into tumors (Wennerberg et al 2014). However, anaplastic thyroid cancer cell lines are known to be sensitive to NK cell-mediated cytolysis in vitro, suggesting thyroid cancers could benefit from immunotherapies that incorporate the recruitment of activated NK cells into the tumor microenvironment (Wennerberg et al 2014).…”

“…Nevertheless, few solid tumors have shown to be responsive to NK cell-mediated immunotherapy due to resistance to NK cell-induced lysis, as well as poor homing and infiltration of NK cells into tumors (Wennerberg et al 2014). However, anaplastic thyroid cancer cell lines are known to be sensitive to NK cell-mediated cytolysis in vitro, suggesting thyroid cancers could benefit from immunotherapies that incorporate the recruitment of activated NK cells into the tumor microenvironment (Wennerberg et al 2014). Additionally, the cells secreted CXCL10 when stimulated with IFN-γ and demonstrated an ability to attract CXCR3 + NK cells (Wennerberg et al 2014) (Parhar et al 2016).…”