Abstract 5127: Eradication of the gut microbiota reduces cancer burden in multiple models by modulating the immune system

Abstract

Abstract Introduction: Bacteria residing in the human body outnumber ‘human' cells and most of these bacteria exist in the gut. This gut microbiome forms a unique and dynamic metagenome which changes with nutrition and even disease state. A growing body of evidence has implicated the role of the gut microbiome in modulating our immune system. We aimed to investigate this association in murine models of cancer. Methods: C57BL/6 mice were either orally given saline or a gut sterilizing cocktail of poorly absorbable broad-spectrum antibiotics. These mice were used to model multiple cancers, viz. subcutaneous injection of melanoma cells derived from Tyr::CreER; Braf V600E/+;Ptenlox5/lox5 mice, subcutaneous injection of pancreatic cancer cells derived from KPC (Kras LSL.G12D/+; p53 R172H/+ ;Pdx::Cre) mice, intrasplenic injection of KPC pancreatic cancer cells and intrasplenic injection of B16-F10 melanoma cells. The tumors were immunophenotyped through flow cytometry and immunostained for multiple antigens. Mice plasma was used for chemokine analysis. To confirm the role of immunity, subcutaneous experiments were repeated in mice carrying a Rag1tm1Mom mutation (RAG1 knockout), thereby having an immature adaptive immune system. Results: Gut microbiome depletion reduced tumor burden across all four subcutaneous and hepatic metastases models. This effect disappeared when experiments were repeated in immunosuppressed RAG1 knockout mice. Antibiotic-treated tumors had increased TNF-secreting macrophages and NKT cells as well a higher number of iNOS staining cells in the microenvironment. Plasma from antibiotic-treated tumor-bearing mice had decreased levels of CXCL12, a chemokine known to cause tumor immunosuppression. Conclusion: Eradication of the gut microbiota decreases tumor burden by activating the anti-cancer immune system Citation Format: Vrishketan Sethi, Saba Kurtom, Mohd Tarique, Bhuwan Giri, Bharti Garg, Shweta Lavania, Anthony Ferrantella, Zoe Malchiodi, Leonor Hellmund, Harrys Charles Jacob, Rajinder Dawra, Sulagna Banerjee, Sabita Roy, Sundaram Ramakrishnan, Ashok Saluja, Vikas Dudeja. Eradication of the gut microbiota reduces cancer burden in multiple models by modulating the immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5127.