Abstract 800: Inflammatory chemokines mediate immune surveillance of intestinal cancer

Abstract Immune system plays a dual role in cancer development and progression. Under conditions of chronic inflammation the repair response initiated by the immune system strongly promotes tumor growth. Epidemiological evidence of increased cancer incidence in organ transplant recipients and immune compromised individuals suggests a critical role for immune surveillance in keeping cancer under control. The cellular and molecular mechanisms that control tumor promoting chronic inflammation or tumor suppressing immune surveillance are unclear. Chemokines direct the migration of leukocytes to the sites of infection or injury and therefore are likely to play a central role in perpetuating tumor promoting chronic inflammation as well as orchestrating tumor eradicating immune surveillance. D6 is a chemokine decoy receptor and an effective scavenger of inflammatory CC-chemokines. D6-knockout (D6-/-) mice showed enhanced inflammation in different models including carcinogen-induced inflammation-promoted skin cancers. In this study, we show that D6-/- mice when bred onto mice with a heterozygous mutation in the adenomatous polyposis coli (ApcMin/+) gene demonstrated reduced intestinal tumor burden and increased survival. A decrease in tumor promoting inflammation is coincidental with increased mast cells and CD8+ T cell activation profiles in tumors from the D6-/-ApcMin/+ mice compared to ApcMin/+ mice. The D6-/-ApcMin/+ mice in the context of the lymphocyte deficient, Rag2-/-background (Rag2-/-D6-/-ApcMin/+), showed a significant increase in tumor burden that is reversed by the adoptively transferred CD8+ and/or CD4+T-lymphocytes from the D6-/-ApcMin/+ mice. Chemokine levels in serum and chemokine receptor expression patterns on lymphocytes from the ApcMin/+ and D6-/-ApcMin/+ mice and the Rag2-/-D6-/-ApcMin/+ mice undergoing adoptive transfer treatments identified the increased levels of ligand-receptor pairs of LTB4/BLT1, CCL2/CCR2, and CXCL9/CXCR3 being critical in promoting tumor suppressive immune surveillance in this spontaneous tumor model. These results show that inflammatory chemokines play a protective role against progression of intestinal cancers by immune surveillance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 800. doi:10.1158/1538-7445.AM2011-800