Abstract B80: Gut commensal bacteria promote antitumor innate immune responses in distant tumors after immunotherapy and chemotherapy.
Authors: Iida Noriho , Stewart Charles , Goldszmid Romina , Dzutsev Amiran , Trinchieri Giorgio 
Published: August 2014

Abstract
Immune system has evolved to fight pathogenic microbes. However, 100 trillion of microbes inhabit in host's gut, skin and urogenital organs without being eliminated and are considered as commensal bacteria. Recent evidences indicated that gut commensal flora give us a benefit by influencing innate and adaptive immune responses. For example, mice treated with oral antibiotics show impaired immune response against respiratory influenza virus and the subsequent increase in the viral load. Thus, commensal flora especially in gut has important roles in development of systemic host immunity.
Tumor tissues have unique inflammatory environment in themselves, and targeting tumors with anti-tumor immune cells is a promising strategy to conquer the cancers. The evidences that gut bacteria positively affect immunity against pathogens prompt us to examine the role of the flora in anti-tumor immunity. This study aimed to determine the effect of gut flora on tumor-associated immune responses after immunotherapy and immunogenic chemotherapy.
To deplete the gut commensal flora, C57BL/6 mice were administered an antibiotic cocktail including neomycin, vancomycin and imipenem in the drinking water, resulting in a 3-log reduction in fecal bacteria. Because CpG oligonucleotide stimulates innate immune cells to produce inflammatory molecules, intratumoral injection of CpG causes destruction of tumors. In mice bearing subcutaneous MCA38 colon carcinoma or B16 melanoma, the antibiotic treatment suppressed the CpG treatment-induced tumor necrosis. TNF is a key effector molecule for tumor destruction in CpG-based therapy. Antibiotic-treated mice showed reduced frequency of tumor-infiltrating TNF-producing myeloid cells after the therapy. Germ-free animals also showed the impaired TNF production. Administration of various single antibiotics revealed that tumor TNF production correlated with the number of gut bacteria. Oral administration of bacterial component lipopolysaccharide (LPS) restored TNF production in antibiotics-treated mice, so LPS is one of the mediators between gut bacteria and the treatment-induced inflammation in the tumors.
Finally, the cytotoxic oxaliplatin-induced immunogenic death of tumor was also impaired in antibiotic-treated mice. Generation of reactive oxygen specices in the tumors is necessary for eradication of the tumors by oxaliplatin treatment. Administration of antibiotics might impair the anti-tumor effect of oxaliplatin by reducing ROS generation from Gr1+ myeloid cells in the tumor.
Altogether, these results demonstrate that optimal immunotherapeutic and chemotherapeutic responses against cancer require an intact commensal flora.
Citation Format: Noriho Iida, Charles Stewart, Romina Goldszmid, Amiran Dzutsev, Giorgio Trinchieri. Gut commensal bacteria promote antitumor innate immune responses in distant tumors after immunotherapy and chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B80.