Abstract 4956: Oral antibiotics act as potent immunotherapeutic agents against pancreatic cancer

Abstract

Abstract Background: Recent reports have elaborated on how the gut microbiota shape vertebrate immune system during ontogeny. Additionally, tumor-promoting inflammation and gut dysbiosis are often associated with multiple cancers including pancreatic ductal adenocarcinoma (PDAC). We sought to investigate the gut microbiota-immune relationship in mouse models of cancer. Methods: To investigate if cancer-associated dysbiosis modulates cancer per se, neonatal mice with unstable, dynamic gut microbiota (guests) were cohoused with either adult cancer-naive mice or adult pancreatic cancer-bearing KPC (KrasG12D/+;Trp53R172H/+;Pdx-1-Cre) mice. After 4 weeks of co-housing, guest mice were subcutaneously implanted with KPC PDAC and monitored for cancer progression. In a parallel series of experiments, tumor progression was compared between control mice and mice given oral antibiotics and also, between germ free mice and conventionalized mice. Later, oral antibiotics were combined with checkpoint inhibitors in preclinical trials of efficacy. Monoclonal antibodies and knockout strains of mice were used to elucidate mechanism. Pancreatic tumors were probed for bacteria. Results: Co-housing with KPC mice significantly increased cancer progression in guest mice compared to that in guest mice co-housed with non-cancer-bearing cagemates. Bowel sterilization dramatically reduced cancer burden in subcutaneous, metastatic, and orthotopic models of pancreatic cancer as well as in subcutaneous and metastatic models of melanoma. Similarly, germ free mice had decreased subcutaneous PDAC burden compared to littermate conventionalized mice. Surprisingly and in findings contradictory to previously published reports, oral antibiotics also potentiated the efficacy of checkpoint inhibitors in shrinking tumors. The tumor decreasing effect of antibiotics disappeared in immunodeficient Rag1-/- mice, wild type mice depleted of IL-17a but not in Tlr4-/- mice. Immunophenotyping further confirmed microbiota-mediated infiltration of immunosuppressive cells inside tumor and antibiotics-mediated activation of intratumoral Th1/Tc1 immunity. Interestingly, pancreatic cancer liver metastases revealed a significant presence of 16S rDNA resembling the gut flora and subcutaneous pancreatic cancer tissue grew viable bacteria on culture medium and this was prevented by oral antibiotics, thereby suggesting a gut-to-tumor translocation of bacteria. Conclusion: Our data suggest that gut microbiota-cancer cross talk is mediated by the immune system and that oral antibiotics may be repurposed as potent anti-cancer immunotherapeutic agents. Citation Format: Vrishketan Sethi, Saba Kurtom, Irina Fernandez, Maria Abreu, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja. Oral antibiotics act as potent immunotherapeutic agents against pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4956.