Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

Anz, David; Rapp, Moritz; Eiber, Stephan; Koelzer, Viktor H.; Thaler, Raffael; Haubner, Sascha; Knott, Max; Nagel, Sarah; Golić, Michaela; Wiedemann, Gabriela M.; Bauernfeind, Franz; Wurzenberger, Cornelia; Hornung, Veit; Scholz, Christoph; Mayr, Doris; Rothenfußer, Simon; Endres, Stefan; Bourquin, Carole

doi:10.1158/0008-5472.can-14-3499

Cited by 67 publications

(51 citation statements)

References 45 publications

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“…immune cells can secrete CCL22, 38,39 in most other types of cancer, however, CCL22 is secreted by tumor-infiltrating immune cells. 40 In HCC, CCL22 upregulation was shown in HBVinfected HCC cell lines and HBVC primary HCC tumors on mRNA level. 35 In HCC, using immunohistology, we did not observe any CCL22 expression by tumor cells in vivo.…”

Section: Discussionmentioning

confidence: 94%

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

et al. 2016

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In cancer patients, immunosuppression through regulatory T cells (Treg) is a crucial component of tumor immune evasion and contributes to disease progression. Tumor-infiltrating Treg in particular suppress local effector T cell responses and are associated with poor prognosis in tumors such as human pancreatic cancer or hepatocellular carcinoma (HCC). The chemokine CCL22 is known to recruit Treg into the tumor tissue and many types of human tumors are known to express high levels of CCL22. The mechanisms leading to intratumoral secretion of CCL22 are so far unknown. We demonstrate here that intratumoral CCL22 is induced in tumor-infiltrating immune cells through cancer cell-derived interleukin-1 (IL-1a). In pancreatic cancer and HCC, CCL22 is produced by intratumoral dendritic cells, while the cancer cells themselves do not secrete CCL22 in vitro and in vivo. Incubation of human peripheral blood mononuclear cells (PBMC) or murine splenocytes with tumor cells or tumor cell supernatants strongly induced CCL22 secretion in vitro. Tumor cell supernatants contained IL-1 and CCL22 induction in PBMC could be specifically prevented by the IL-1 receptor antagonist anakinra or by transfection of tumor cell lines with IL-1 siRNA, leading to a suppression of Treg migration. In conclusion, we identify here tumor cell-derived IL-1a as a major inducer of the Treg attracting chemokine CCL22 in human cancer cells. Therapeutic blockade of the IL-1 pathway could represent a promising strategy to inhibit tumorinduced immunosuppression.

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Section: Discussionmentioning

confidence: 94%

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

et al. 2016

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“…18 C-C motif chemokine 22 (CCL22), also known as macrophage-derived chemokine, was found abundantly expressed in many types of malignancies. [19][20][21][22][23] Evidence obtained from studies suggested that CCL22-CCR4 signaling axis could help peritoneal tumors to migrate, survive, and establish cell cluster-type metastasis, in contrast to later stages of tumor development, in which CCL22 activation was needed. 24 Moreover, according to recent studies, tumor cells could transform CD4 C T cells into Tregs, resulting in high risk of immune escape.…”

Section: Introductionmentioning

confidence: 99%

C-C motif chemokine 22 predicts postoperative prognosis and adjuvant chemotherapeutic benefits in patients with stage II/III gastric cancer

Líu

et al. 2018

OncoImmunology

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Immune molecules, which have been found to be important in tumor microenvironment, seem prospective in tumor therapy, but they are still not effective enough to use in clinical practice. C-C motif chemokine 22 (CCL22) exists in various malignancies and correlates with migration of regulatory T cells, but its clinical significance in gastric cancer is still unclear. In this study, a combined data set of 466 patients with gastric cancer after surgical resection, comprised of a discovery (n = 319) and a validation data set (n = 147), was enrolled. CCL22 expression was assessed by immunohistochemical staining and we evaluated prognostic values of CCL22 staining and clinical outcomes with use of Kaplan-Meier curve and Multivariate Cox regression analysis. Positive CCL22 expression predicted adverse overall survival independent of traditional pathological grade. Multivariate analysis defined CCL22 and TNM stage as two independent prognostic factors for overall survival. Besides, in patients with TNM stage II/III disease, the rate of overall survival was higher among patients with CCL22-positive tumors who were treated with 5-fluorouracil based adjuvant chemotherapy than that among those who were not ( = 0.012, < 0.001 and < 0.001, in discovery, validation and combined data set). But for these with CCL22-negative tumors, whether to undergo adjuvant chemotherapy showed no statistical significance ( = 0.595, = 0.085 and P = 0.252, respectively). To conclude, CCL22 was identified as an independent adverse prognostic immunobiomarker for patients with gastric cancer after surgery, which is associated with tumor-infiltrating immunocytes and could be incorporated into TNM staging system to redefine a high-risk subgroup who were more likely to benefit from 5-fluorouracil based adjuvant chemotherapy.

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“…Autoimmunity/inflammation disease: Tregs play an essential role in the prevention of autoimmune diseases and the maintenance of peripheral tolerance [1, 63] in cancer therapy [15, 64], transplantation tolerance [9, 19, 65, 66], inflammatory bowel disease [67], allergy/asthma [68, 69], liver disease [70], blood diseases [71], and dermatological diseases [72]. …”

Section: Resultsmentioning

confidence: 99%

Global Regulatory T-Cell Research from 2000 to 2015: A Bibliometric Analysis

Yin

Dongying

2016

PLoS ONE

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We aimed to analyze the global scientific output of regulatory T-cell (Treg) research and built a model to qualitatively and quantitatively evaluate publications from 2000 to 2015. Data were obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on January 1, 2016. The bibliometric method and Citespace III were used to analyze authors, journals, publication outputs, institutions, countries, research areas, research hotspots, and trends. In total, we identified 35,741 publications on Treg research from 2000 to 2015, and observed that the annual publication rate increased with time. The Journal of Immunology published the highest number of articles, the leading country was the USA, and the leading institute was Harvard University. Sakaguchi, Hori, Fontenot, and Wang were the top authors in Treg research. Immunology accounted for the highest number of publications, followed by oncology, experimental medicine, cell biology, and hematology. Keyword analysis indicated that autoimmunity, inflammation, cytokine, gene expression, foxp3, and immunotherapy were the research hotspots, whereas autoimmune inflammation, gene therapy, granzyme B, RORγt, and th17 were the frontiers of Treg research. This bibliometric analysis revealed that Treg-related studies are still research hotspots, and that Treg-related clinical therapies are the research frontiers; however, further study and collaborations are needed worldwide. Overall, our findings provide valuable information for the editors of immunology journals to identify new perspectives and shape future research directions.

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Suppression of Intratumoral CCL22 by Type I Interferon Inhibits Migration of Regulatory T Cells and Blocks Cancer Progression

Cited by 67 publications

References 45 publications

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells

C-C motif chemokine 22 predicts postoperative prognosis and adjuvant chemotherapeutic benefits in patients with stage II/III gastric cancer

Global Regulatory T-Cell Research from 2000 to 2015: A Bibliometric Analysis

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