Role of probiotic Lactobacillus reuteri in orchestrating systemic anti-tumor immunity

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Project Summary The gut microbiome exerts a profound impact on systemic immunity in health and in complex diseases, such as cancer. Numerous studies highlighted the robust anti-carcinogenic ability of the gut microbiome to regulate extra-intestinal (systemic) anti-tumor immunity. Cytotoxic interferon-g producing CD8 T cells (Tc1 cells) play a central role in mediating anti-tumor immunity by potently killing tumor cells and affecting immune checkpoint blockade therapies. Bacterial supplements (probiotics) have been used to promote health for more than a century and are gaining traction as a crucial component in successful cancer immunotherapy in mice and humans. Yet, the underlying mechanisms how probiotics orchestrate systemic anti-tumor immunity and modulate cancer immunotherapy outcome remain incompletely understood. Lactobacillus reuteri (L. reuteri) is one of the most frequently used probiotics and plays a beneficial role in colon cancer. Yet, the role of L. reuteri in modulating systemic anti-tumor Tc1 immunity remains undefined. The gut microbiota plays a fundamental role in the maintenance of intestinal barrier integrity and disruption of the gut microbial community (dysbiosis) constitutes a major risk factor for several forms of intestinal and non-intestinal cancers. Moreover, intestinal barrier dysfunction and gut bacterial translocation are associated with complex inflammatory diseases including cancer. We recently showed that gut bacterial translocation resulting from microbiota-mediated intestinal barrier dysfunction drives preleukemic myeloid malignancy in a mouse model of myeloid cancer. Microbial signals were identified in intestinal as well as systemic tumors, which serve both pro- and anti- tumorigenic functions. However, the presence of viable gut bacteria in systemic tumors and the underlying mechanisms how tumor intrinsic microbes affect tumor immunity remain ill defined. Our preliminary data suggest that orally gavaged L. reuteri drives systemic Tc1 cell immunity in melanoma tumor bearing mice and is associated with transient dissemination of viable L. reuteri from the intestine to secondary lymphoid organs and melanoma tumors. Moreover, we have preliminary indications that melanoma tumor-formation induces gut barrier dysfunction, which suggests a possible mechanism how orally gavaged L. reuteri can reach gut-distal melanoma tumors. Based on well documented findings of the systemic impact of gut microbes during melanoma, together with our preliminary data, our overarching hypothesis is that the probiotic L. reuteri mediates systemic anti-tumor Tc1 cell immunity and facilitates cancer immunotherapy in melanoma (AIM 1) by translocation of viable L. reuteri from the gut to gut-distal melanoma tumors (AIM 2). We will test this hypothesis and dissect the underlying mechanisms how L. reuteri modulates anti-cancer immunity and will define the mechanisms how L. reuteri gains access to gut-distal tumors. The long-term goal of this proposal is to provide rational approaches to control systemic tumor immunity by modulating the gut microbiota during cancer.