CD3−CD16−CD56brightImmunoregulatory NK Cells are Increased in the Tumor Microenvironment and Inversely Correlate with Advanced Stages in Patients with Papillary Thyroid Cancer

Gogali, Foteini; Paterakis, George; Rassidakis, George Z.; Liakou, Chrysoula; Liapi, Charis

doi:10.1089/thy.2012.0560

Cited by 64 publications

(59 citation statements)

References 53 publications

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“…Previous studies which have examined NK cells in the context of tumor development have described these cells as non-functional due to their lack of activation markers and increased expression of inhibitory receptors 12,[26][27][28] . In the context of our work, we believe that these cells are not necessarily nonfunctional but are at a different stage in their development within tumors.…”

Section: Discussionmentioning

confidence: 99%

The breast tumor microenvironment alters the phenotype and function of natural killer cells

et al. 2015

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Natural killer (NK) cells are innate immune cells with the ability to identify and eliminate transformed cells. However, within tumors, many studies have described NK cells as non-functional. The developmental stage of tumor-associated NK cells and how this may relate to functionality has not been explored. We examined the developmental state of NK cells from polyoma middle T antigen (pyMT) transgenic mouse (MMTV-pMT) breast tumors. In pyMT tumors, NK cells were immature as evidenced by their decreased expression of DX5 and their CD27 low CD11b low phenotype. These immature NK cells also had increased expression of NKG2A and expressed low levels of NKp46, perforin, and granzyme B. In contrast, splenic NK cells isolated from the same mice maintained their maturity and their expression of activation markers. To delineate whether the tumor microenvironment directly alters NK cells, we adoptively transferred labeled NK cells and followed their activation status in both the spleen and the tumor. NK cells that arrived at the tumor had half the expression of NKp46 within three days of transfer in comparison to those which arrived at the spleen. In an effort to modify the tumor microenvironment and assess the plasticity of intratumoral NK cells, we treated pyMT tumors with IL-12 and anti-TGF-b. After one week of treatment, the maturity of tumor-associated NK cells was increased; thus, indicating that these cells possess the ability to mature and become activated. A better understanding of how NK cells are modified by the tumor microenvironment will help to develop strategies aimed at bolstering immune responses against tumors.

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Section: Discussionmentioning

confidence: 99%

The breast tumor microenvironment alters the phenotype and function of natural killer cells

et al. 2015

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“…Also, the percentage of CD56 dim NK cells was lower in the tumor than in in peripheral blood. Gogali and colleagues have recently reported that in patients with PTC, CD56 dim NK cells were lower in PTC tissue than in peripheral blood, although the ratio of CD56 dim NK cells in the PTC-infiltrating NK cell population correlated positively with disease stage (38). There are several possible explanations for the skewed ratio between CD56 bright and CD56 dim NK cells in tumors.…”

Section: Discussionmentioning

confidence: 99%

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Wennerberg

Pfefferle

Ekblad

et al. 2014

Clinical Cancer Research

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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.

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“…These studies provide insights on how BRAF V600E mutant determines cancer initiation, progression, and invasiveness in PTCs and may provide new therapeutic targets for the treatment of aggressive PTCs (Bommarito et al 2011). CD3KCD16KCD56bright immunoregulatory NK cells are increased in the tumor microenvironment and were found to be inversely correlated with advanced stages in patients with PTC (Gogali et al 2013). In a recent analysis of four new ATC cell lines, Marlow et al (2010) have reported that suppressed RHOB was implicated as a molecular target for the treatment of ATCs, because drugs like romidepsin, a histone deacetylase inhibitor, was able to inhibit cell proliferation and upregulate RHOB in these new ATC cell lines.…”

Section: Role Of the Microenvironmentmentioning

confidence: 95%

Cancer stem-like cells and thyroid cancer

Guo¹,

Hardin²,

Lloyd³

2014

Endocrine Related Cancer

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Thyroid cancer is one of the most rapidly increasing malignancies. The reasons for this increase is not completely known, but increases in the diagnosis of papillary thyroid microcarcinomas and follicular variant of papillary thyroid carcinomas along with the enhanced detection of well-differentiated thyroid carcinomas are probably all contributing factors. Although most cases of well-differentiated thyroid carcinomas are associated with an excellent prognosis, a small percentage of patients with well-differentiated thyroid carcinomas as well as most patients with poorly differentiated and anaplastic thyroid carcinomas have recurrent and/or metastatic disease that is often fatal. The cancer stem-like cell (CSC) model suggests that a small number of cells within a cancer, known as CSCs, are responsible for resistance to chemotherapy and radiation therapy, as well as for recurrent and metastatic disease. This review discusses current studies about thyroid CSCs, the processes of epithelial-to-mesenchymal transition (EMT), and mesenchymal-to-epithelial transition that provide plasticity to CSC growth, in addition to the role of microRNAs in CSC development and regulation. Understanding the biology of CSCs, EMT and the metastatic cascade should lead to the design of more rational targeted therapies for highly aggressive and fatal thyroid cancers.

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CD3⁻CD16⁻CD56^brightImmunoregulatory NK Cells are Increased in the Tumor Microenvironment and Inversely Correlate with Advanced Stages in Patients with Papillary Thyroid Cancer

Abstract: CD3(-)CD16(-)CD56(bright) NK cell infiltration seems to be associated with PTC progression. These findings contribute to a better understanding of the immune response in PTC and may lead to novel immunotherapeutic approaches in these patients.

Cited by 64 publications

References 53 publications

The breast tumor microenvironment alters the phenotype and function of natural killer cells

The breast tumor microenvironment alters the phenotype and function of natural killer cells

Human Anaplastic Thyroid Carcinoma Cells Are Sensitive to NK Cell–Mediated Lysis via ULBP2/5/6 and Chemoattract NK Cells

Cancer stem-like cells and thyroid cancer

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