Abstract A123: Modulation of immune cell trafficking into human colorectal cancer by gut microbiota

Colorectal cancer (CRC) is a leading cause of cancer-related death. CRC infiltration by immune cells, including cytotoxic CD8+ T cells (CTLs), IFN-gamma-producing T-helper 1 cells (Th1), Foxp3+ regulatory T cells (Tregs) and CD16+ MPO+ neutrophils, is associated with favorable prognosis. However, chemokines driving these cell populations into the tumor site, their cellular sources and their microenvironmental triggers remain to be elucidated. We investigated the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis. Analysis of freshly excised specimens of CRC and adjacent healthy colonic tissues revealed that tumor infiltration by beneficial immune cells is associated with the expression of four main chemokine patterns: 1) CCL3, CCL5, CCL8, CXCL9, CXCL10, and CXCL12 for CTLs; 2) CCL5, CCL22, CXCL9 and CXCL12 correlating with CRC infiltration by Th1; 3) CCL22 and CXCL12 attracting Tregs; 4) CXCL2 and CXCL5, promoting chemotaxis of CD16+ MPO+ myeloid cells. Most of identified chemokines were found to be expressed, although at different levels, in primary CRC cells purified from tumor specimens and from xenografts generated upon injection of CRC cells in immunodeficient mice. Notably, chemokine expression levels in orthotopic xenografts, developed upon intracecal injection of tumor cells, were significantly higher as compared to those of subcutaneous tumors. Antibiotic treatment of tumor bearing mice drastically reduced chemokine expression in orthotopic xenografts, thus suggesting a role for commensal bacteria in chemokines induction in tumor cells. Importantly, human CRC samples characterized by high expression of chemokine and immune cell markers, displayed significantly higher bacterial loads, as compared to samples showing low chemokine expression and immune cell infiltration. Furthermore, bacterial loads significantly correlated with expression of CCL3 and CCL5, and Th1 infiltration. These data suggest that stimuli derived from gut flora components may trigger chemokine production in CRC tissues thus leading to tumor infiltration by beneficial immune cells. Note: This abstract was not presented at the conference. Citation Format: Eleonora Cremonesi, Francesca Amicarella, Jesus Francisco Glaus Garzon, Valeria Governa, Manuele Giuseppe Muraro, Valentina Mele, Elisabetta Padovan, Daniel Oertli, Paul Zajac, Giulio Cesare Spagnoli, Lubor Borsig, Giandomenica Iezzi. Modulation of immune cell trafficking into human colorectal cancer by gut microbiota [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A123.