IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Ma, Huiyuan; Whitters, Matthew J.; Konz, Richard F; Senices, Mayra; Young, Deborah; Grusby, Michael J.; Collins, T. Mary; Dunussi‐Joannopoulos, Kyriaki

doi:10.4049/jimmunol.171.2.608

Cited by 162 publications

(158 citation statements)

References 50 publications

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“…Our work demonstrating the concurrent production of high levels of granzyme B by nearly all cells of a highly cytolytic effector population that is uniformly unable to produce IFN-␥, provides the strongest evidence to date for the uncoupling of cytotoxicity and IFN-␥ secretion within a single CD8 T cell. Consistent with the results described here, Ma et al (21) have described clearance of an IL-21-secreting tumor by a CD8-and NK cell-dependent mechanism requiring perforin but not IFN-␥. Furthermore, we have observed an E.G7 tumor-infiltrating, Ag-specific population of granzyme B high, IFN-␥ negative CD8 effector cells (J. M. Curtsinger, M. Y. Gerner, D. C. Lins, and M. F. Mescher, unpublished data).…”

Section: Discussionsupporting

confidence: 80%

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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IL-21, the most recently described member of the common γ-chain cytokine family, is produced by activated CD4 T cells, whereas CD8 T cells express the IL-21 receptor. To investigate a possible role for IL-21 in the priming of naive CD8 T cells, we examined responses of highly purified naive OT-I CD8 T cells to artificial APCs displaying Ag and B7-1 on their surface. We found that IL-21 enhanced OT-I clonal expansion and supported development of cytotoxic effector function. High levels of IL-2 did not support development of effector functions, but IL-2 was required for optimal responses in the presence of IL-21. IL-12 and IFN-α have previously been shown to support naive CD8 T cell differentiation and acquisition of effector functions through a STAT4-dependent mechanism. Here, we show that IL-21 does not require STAT4 to stimulate development of cytolytic activity. Furthermore, IL-21 fails to induce IFN-γ or IL-4 production and can partially block IL-12 induction of IFN-γ production. CD8 T cells that differentiate in response to IL-21 have a distinct surface marker expression pattern and are characterized as CD44high, PD-1low, CD25low, CD134low, and CD137low. Thus, IL-21 can provide a signal required by naive CD8 T cells to differentiate in response to Ag and costimulation, and the resulting effector cells represent a unique effector phenotype with highly effective cytolytic activity, but deficient capacity to secrete IFN-γ.

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Section: Discussionsupporting

confidence: 80%

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

Casey

Mescher

2007

The Journal of Immunology

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“…60 Other NK cell activators, such as IL-12, IL-15, IL-18 and IL-21, have been successfully tested in preclinical cancer models as part of various vaccination strategies. 92,93 In the presence of IL-15 and hydrocortisone (HC), autologous NK cells can be activated and expanded in vitro, and these cells are effective in vivo in a lung metastasis mouse model which accumulated in lung tissue and were retained in the tumor-bearing site for more than 3 days. Extremely high IL-15 doses were necessary to observe any meaningful antitumor effects in vivo.…”

Section: Conception Of Nk Cellsmentioning

confidence: 99%

NK cell-based immunotherapy for malignant diseases

et al. 2013

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Natural killer (NK) cells play critical roles in host immunity against cancer. In response, cancers develop mechanisms to escape NK cell attack or induce defective NK cells. Current NK cell-based cancer immunotherapy aims to overcome NK cell paralysis using several approaches. One approach uses expanded allogeneic NK cells, which are not inhibited by self histocompatibility antigens like autologous NK cells, for adoptive cellular immunotherapy. Another adoptive transfer approach uses stable allogeneic NK cell lines, which is more practical for quality control and large-scale production. A third approach is genetic modification of fresh NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from various sources, including peripheral or cord blood cells, stem cells or even induced pluripotent stem cells (iPSCs), and a variety of stimulators can be used for large-scale production in laboratories or good manufacturing practice (GMP) facilities, including soluble growth factors, immobilized molecules or antibodies, and other cellular activators. A list of NK cell therapies to treat several types of cancer in clinical trials is reviewed here. Several different approaches to NK-based immunotherapy, such as tissue-specific NK cells, killer receptor-oriented NK cells and chemically treated NK cells, are discussed. A few new techniques or strategies to monitor NK cell therapy by non-invasive imaging, predetermine the efficiency of NK cell therapy by in vivo experiments and evaluate NK cell therapy approaches in clinical trials are also introduced.

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“…Considering the profound effects of IL-21 on T and NK cells and the proven antitumor effects of another gammachain cytokine (IL-2), it is not surprising that IL-21 has antitumor effects (Wang et al, 2003). These have been observed in animal models including melanoma, sarcoma, and bladder and renal cell carcinoma (Ma et al, 2003;Furukawa et al, 2006;Søndergaard et al, 2007). Through depletion studies, the antitumor activity of IL-21 was shown to depend on NK cells or CD8+ T cells, or both, depending on the tumor model.…”

Section: Discussionmentioning

confidence: 97%

Diagnostic Value of Interleukin 21 and Carcinoembryonic Antigen Levels in Malignant Pleural Effusions

Bunjhoo¹,

Wang²,

Chen³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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The aim of this study was to evaluate the diagnostic value of interleukin 21(IL-21) and carcinoembryonic antigen (CEA) in tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs). Pleural effusion samples from 103 patients were classified on the basis of diagnosis as TPE (n=51) and MPE (n=52). The concentration of IL-21 was determined by ELISA. Lactate dehydrogenase (LDH), adenosine dehydrogenase (ADA) and CEA levels were also determined in all patients. A significant difference was observed in the levels of ADA and CEA (P<0.01), but not in the levels of LDH (P>0.05) between TPE and MPE. The concentration of IL-21 in MPE was significantly higher compared to TPE (P<0.01). With a threshold value of 4.32 pg/ml, IL-21 had a sensitivity of 76.9% (40/52) and a specificity of 80.4% (41/51). Combined detection of IL-21 and CEA had a sensitivity of 69.2% (36/52) and a specificity of 92.2% (47/51). These two markers can contribute to the differential diagnosis of MPEs.

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IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-γ

Cited by 162 publications

References 50 publications

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

IL-21 Promotes Differentiation of Naive CD8 T Cells to a Unique Effector Phenotype

NK cell-based immunotherapy for malignant diseases

Diagnostic Value of Interleukin 21 and Carcinoembryonic Antigen Levels in Malignant Pleural Effusions

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