期刊
CLINICAL CANCER RESEARCH
卷 20, 期 22, 页码 5733-5744出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-0291
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资金
- The American Thyroid Association
- The Swedish Research Council [522-208-2377]
- Swedish Cancer Society [CAN 2012/474]
- FP7 Marie Curie re-integration grant [246759]
- Karolinska Institutet
- Jeanssons Stiftelser
- Ake Wibergs Stiftelse
- Magnus Bergvalls Stiftelse
- Fredrik och Ingrid Thurings Stiftelse
- Stiftelsen Clas Groschinskys Minnesfond
- Cancer Society in Stockholm [121132]
- Swedish Society of Medicine [325751]
- Stockholm City Council
- King Gustaf V Jubilee Fund
- Governmental funding of clinical research within the NHS
- Region of Scania RD funding
- Foundations of the University Hospital of Lund
- Gunnar Nilsson Cancer Foundation
- Berta Kamprad Foundation for Investigation and Control of Cancer Diseases
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. (C) 2014 AACR.
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