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Deficiency of the Immunostimulatory Cytokine IL-21 Promotes Intestinal Neoplasia
Mia Shapiro1,2; Bisweswar Nandi1,2; Rao H. Prabhala1,2,4; Gabriel Gonzalez1; Qin Huang1,2,3; Natasha Y. Frank1,3; Nikhil C. Munshi1,2,3,4; Jason S. Gold1,2,3
1VA Boston Healthcare System; 2Harvard Medical School; 3Brigham and Women's Hospital; 4Dana Farber Cancer Institute

Background: Interest in the use of the cytokine IL-21 as an immunotherapeutic agent grew out of success with IFN&947; and IL-2 in melanoma. IL-21 increases B and T cell proliferation and survival as well as granzyme B-mediated cytotoxicity of NK and T cells. The role of IL-21 in spontaneous intestinal carcinogenesis has not been fully explored.

Methods: Mice with a knockout of IL-21 (KO) were bred with APCMIN/+ (MIN) mice. MIN mice spontaneously develop intestinal adenomas. C57/BL6 mice (WT) were used as controls. At 15 weeks, polyps were measured and counted. Mouse ileum was preserved for embedding and immunohistochemical staining or q-RT-PCR.

Results: Polyp-bearing ileum from MIN mice had a five-fold increase in IL-21 expression by q-RT-PCR as compared to the non-polyp bearing ileum of WT mice. IL-21KO-MIN mice had increased intestinal polyp number and tumor load as compared to MIN mice with functional IL-21 (Figure). KO-MIN mice had fewer T cells and B cells in the ileum than MIN mice. The number of granzyme B+ cells was also lower in KO-MIN mice (Figure).

Conclusion: Adenoma development is associated with upregulation of intestinal IL-21 in a mouse model of spontaneous intestinal neoplasia. Deficiency of IL-21 leads to accelerated tumor development along with a decrease in B and T cells and a drop in the number of granzyme B-releasing cells. These data support the hypothesis that IL-21 is involved in mediating spontaneous anti-tumor immunity controlling adenoma development.


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