Abstract 6201: Live biotherapeutic MRx0518 as a modulator of immune responses in intestinal tissue and breast tumor microenvironment

Abstract

Abstract Introduction: The human gut microbiota plays a role in modulating both intestinal and systemic immunity. Its importance in regulating anti-tumorigenic responses is now being explored, supported by evidence that the functional profile of the gut microbiome influences response to cancer immunotherapy. We previously demonstrated that the gut microbiome-derived Live Biotherapeutic Enterococcus gallinarum, MRx0518, had strong immunostimulatory properties in vitro, and was a TLR5 and NF-κB activator. We further investigated whether this bacterial strain displayed anti-tumor efficacy in a murine mammary carcinoma model. Experimental procedure: The EMT-6 syngeneic mammary carcinoma tumor model was used to investigate the anti-tumor activity of MRx0518. Female BALB/c mice were engrafted subcutaneously at day 0 with tumor cells, and tumor volumes and body weights were measured twice a week until termination. Animals were orally dosed daily with MRx0518 from D-14 until the end of experiments. Faeces, blood and tissues (ileum, colon, tumor) were collected at study start, midpoint and/or end. NanoString technology was used to study gene expression and the associated pathways modulated, and to evaluate the relative abundance of specific immune cell populations in the tumor, ileum and colon. The plasma and tumour cytokine/chemokine profiles were evaluated using a fluorescent bead-based (Luminex) immunoassay kit. 16S rRNA-based metagenomic analysis was performed on stool samples. Results: MRx0518 monotherapy induces a reduction in EMT-6 murine tumor burden. MRx0518 therapeutic activity was associated with upregulation of genes involved in immune cell adhesion and migration, such as Cd38 and Clec14a, and increased Tlr5 expression in the tumor. At the intestinal level, lymphoid compartment and cell adhesion pathways were upregulated, in particular Spp1, Cd19, Ms4a1 and Sell genes. Immune cell populations including NK, T cells and cytotoxic cells were increased by MRx0518 treatment in both intestinal tissue and the tumor microenvironment. Conclusion: Our preclinical studies demonstrate that the ability of oral MRx0518 to reduce tumor growth in the EMT-6 syngeneic model of breast cancer is mainly related to changes in innate (increase in NK cells, upregulation of tumour TLR5 expression) and adaptive (increase of ratio CD8+ T cells/FoxP3+ regulatory T cells) immune responses locally in the gut but also in the distal tumour microenvironment. In this context, MRx0518 monotherapy and combination with immune checkpoint inhibitors is a promising therapeutic approach for enhancing antitumor immune responses. Citation Format: Jean-Francois Mirjolet, Sylvie Maubant, Sophie Bourdot, Loîc Morgand, Aurélie Couturier-Maillard, Delphine Lauté-Caly, Emma Hennessy, Lorenzo Pavarini, Maria Christofi, Tamas Sukei, Elisabeth Logan, Marsilio Adriani, Imke Mulder. Live biotherapeutic MRx0518 as a modulator of immune responses in intestinal tissue and breast tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6201.