Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts

Ugai, Shin-ichi; Shimozato, Osamu; Kawamura, Kiyoko; Wang, Yanqing; Yamaguchi, Taketo; Saisho, Hiromitsu; Sato, Shigeru; Tagawa, Masatoshi

doi:10.1038/sj.cgt.7700552

Cited by 72 publications

(43 citation statements)

References 11 publications

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“…The decreased adenoma burden seen in IL-21-deficient animals is in line with previous work showing that colon cancers engineered to overexpress IL-21 exhibit decreased growth and were even found to regress in subcutaneous tumor challenge models. 4,17 Our results, however, contradict previous studies examining the relationship between IL-21 and intestinal tumorigenesis induced by dextran sulfate sodium (DSS) and azoxymethane (AOM). 10,11,18 DSS and AOM are commonly used to mimic colitis-associated colon cancer.…”

Section: Intestinal Polyposis Is Increased In Il-21ko-apc Min/c Micecontrasting

confidence: 97%

“…20 In experiments where IL-21 was overexpressed in subcutaneous tumor challenge models, IL-21 was found to increase infiltration of T and NK cells 4 and to enhance lysis of tumor cells by splenocytes. 17 Furthermore, increased expression of IL-21 has been correlated with dramatically improved disease-free survival in human colorectal cancer. 23 Deficiency of IL-21 increases the tendency to polarize to the Th17 phenotype While IL-21 is well known to enhance cytotoxic lymphocyte responses and antitumor immunity, multiple studies, using predominantly in vitro experiments, have indicated that IL-21 not only promotes, but also sustains the Th17 pathway.…”

Section: 6mentioning

confidence: 99%

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Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

et al. 2016

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IL-21 has reported activity in promoting both Th1 and Th17 immune responses. Its role in sporadic human colorectal cancer is unknown. We aimed to delineate the role of IL-21 in a model of sporadic intestinal carcinogenesis. We found that in APC MIN/C mice, ablation of IL-21 increased intestinal tumorigenesis. Expression of pro-inflammatory Th17-associated genes, including RORgt and IL-17A, was increased in the intestine in the absence of IL-21, while expression of antitumor Th1-associated genes Tbet, IFNg, granzyme B, and perforin was decreased. Similarly, the IL-21-deficient APC MIN/C mouse intestines had fewer infiltrating T cells as well as decreased effector memory T cells, NK cells, and granzyme B-expressing cells. Finally, our data suggest that IL-21 impairs Th17 immune responses as mesenteric lymph nodes from IL-21-deficient mice had increased IL-17A expression, and naive helper T cells from IL-21-deficient mice were more prone to differentiate into IL-17A-secreting cells.

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Section: Intestinal Polyposis Is Increased In Il-21ko-apc Min/c Micecontrasting

confidence: 97%

Section: 6mentioning

confidence: 99%

Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

et al. 2016

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“…To our knowledge IL-21 is the first cytokine so far that has been shown to induce autoimmune depigmentation and thus vigorous anti-tumor response. By the time we submitted this manuscript, Ugai et al (50) published similar findings in murine colon carcinoma models. Their report also highlighted the importance of IL-21 in inducing effective antitumor responses through NK and CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 65%

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

Ma¹,

Whitters²,

Konz³

et al. 2003

The Journal of Immunology

162

148

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IL-21 is a key factor in the transition between innate and adaptive immune responses. We have used the cytokine gene therapy approach to study the antitumor responses mediated by IL-21 in the B16F1 melanoma and MethA fibrosarcoma tumor models in mice. Retrovirally transduced tumor cells secreting biologically functional IL-21 have growth patterns in vitro similar to that of control green fluorescent protein-transduced cells, but are completely rejected in vivo. We show that IL-21 activates NK and CD8+ T cells in vivo, thus mediating complete rejection of poorly immunogenic tumors. Rejection of IL-21-secreting tumors requires the presence of cognate IL-21R and does not depend on CD4+ T cell help. Interestingly, perforin, but not IFN-γ or other major Th1 and Th2 cytokines (IL-12, IL-4, or IL-10), is required for the IL-21-mediated antitumor response. Moreover, IL-21 results in 50% protection and 70% cure of nonimmunogenic tumors when given before and after tumor challenge, respectively, in C57BL/6 mice. We conclude that IL-21 immunotherapy warrants clinical evaluation as a potential treatment for cancer.

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“…Interferon gamma production also shows anti-tumor effects, however, this role is not supposed to be as strong as cell mediated cytotoxicity [154][155][156].…”

Section: Other Interleukinsmentioning

confidence: 99%

Emerging Role of Interleukins in Cancer Treatment

Razavi¹,

Allen²

2014

Immunome Res

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Expression of the interleukin-21 gene in murine colon carcinoma cells generates systemic immunity in the inoculated hosts

Cited by 72 publications

References 11 publications

Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

Deficiency of the immunostimulatory cytokine IL-21 promotes intestinal neoplasia via dysregulation of the Th1/Th17 axis

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

Emerging Role of Interleukins in Cancer Treatment

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