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Leptin Receptor–Related Immune Response in Colorectal Tumors: The Role of Colonocytes and Interleukin-8

¹ Université Paris Est (XII) and AP-HP, GIT Cancer Study Team INSERM-CIC; Departments of ² Pathology, ³ Biological Immunology, and ⁴ Gastroenterology, Henri Mondor Hospital, Creteil, France; and ⁵ Institut National de la Santé et de la Recherche Médicale, U773, CRB3, Xavier Bichat Hospital, Paris, France

Requests for reprints: Iradj Sobhani, Service d'Hépato-gastroentérologie, CHU Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94100 Créteil, France. Phone: 33-1-49-81-23-62; Fax: 33-1-49-81-23-52; E-mail: iradj.sobhani{at}hmn.aphp.fr.

Key Words: Cytotoxic cell • leptin receptor • Perforin

We have shown that ObRb, the leptin receptor, is overexpressed in colorectal cancer cells, and that this may influence the patients' outcome. We investigated colonocytes as leptin targets and characterized their pivotal role in antitumor immune response. Cytokine and chemokine mRNAs in HT29 cells were measured by targeted arrays. In vitro, normal colonocytes and human colon cancer cells (HT29, Caco-2, SW480, and HCT116) were used to investigate ObRb transduction system and cytokine releases. Animal colonocytes and CD8 splenocytes and human HT29, HCT116, and CD8⁺ cells from blood donors were used to investigate the lymphocyte response to the colonocytes when stimulated by leptin. Leptin-induced cytokine releases in the normal colonic mucosa and tumor growth and cytokine releases within tumors in vivo were measured in male rats and nude mice, respectively. Statistical analysis was done by Fisher's exact and Mann-Whitney U tests. Various cytokines and their receptors were produced in normal and tumoral colonocytes in response to leptin by increasing nuclear factor-B activation. Interleukin-8 (IL-8) was the main cytokine produced in vitro. The levels of IL-8 and its receptor, CXCR1, were higher in tumors than in homologous normal mucosa. Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8⁺ T cells in vitro. Leptin triggers an inflammatory response in tumor tissue by directly stimulating colonocytes, which can recruit T cytotoxic cells in the tumor microenvironment. [Cancer Res 2008;68(22):9423–32]

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