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P001. Ulcerative colitis-associated carcinogenesis depends on alternatively activated “M2 macrophages” – from mice to men

M. Worlicek1, P. Ruemmele2, H.J. Schlitt1, S. Fichtner-Feigl1

1University Medical Center Regensburg, Department of Surgery, Regensburg, Germany; 2University Medical Center Regensburg, Department of Pathology, Regensburg, Germany

Background: The pathogenesis of human ulcerative colitis (UC) is characterized by the presence of IL‑13-producing Natural Killer T cells (NKT cells). One major complication of UC is the development of colitis-associated colorectal cancer. In these studies we determined the role of alternatively activated “M2 macrophages” in a new mouse model of colitis-associated carcinogenesis. Further, we verified these results through immunological analysis of surgical specimens obtained from patients with UC-associated colon cancer.

Methods: Studies were performed using a mouse model for colitis-associated carcinogenesis based on chronic Oxazolone-colitis in combination with an initial i.p. azoxymethane (AOM) injection in female BALB/c mice. We observed chronic intestinal inflammation lasting for 12 weeks in mice repeatedly administered Oxazolone. Surgical specimens with UC-associated colon cancer were analyzed by flow cytometry and immunohistochemistry.

Results: We could show that Oxazolone-colitis was mediated by colonic alpha-galactosyl-ceramide+CD1+ NKT-cells producing IL‑13 and therefore resembles the immunological characteristics of human UC. Colon cancer development in this model was dependent on F4/80+CD11bhighGr1low macrophages producing IL‑6 and EGF. Those cells inherited phenotypic characteristics of IL‑13-stimulated alternatively-activated “M2 macrophages”. To elucidate the importance of these “M2 macrophages”, we conducted bone marrow chimera studies and demonstrated that innate immune signaling through MyD88 in “M2 macrophages” is the key event for the production of tumor supporting factors like IL‑6 and EGF. In surgical specimens obtained from patients with UC-associated colon cancer we verified those experimental findings. We consistently found a dense accumulation of IL‑13-producing NKT cells inside the tumors. In addition, in this IL‑13-dominated tumor micromilieu CD14+ and CD68+ antigen-presenting cells accumulated intensively and those antigen-presenting cells demonstrated an alternatively activated “M2 phenotype” by the expression of CD163 and CD205.

Conclusions: We could demonstrate that in an experimental UC model, as well as in human UC, pathogenic IL‑13-producing NKT cells accumulate in the tumor micromilieu of UC-associated colon cancers. This immunologic situation inside the tumor microenvironment of mice and men induces tumor promoting M2 macrophages. Therefore M2 macrophages represent a potential target for future therapeutic strategies.