Commensal microbe elicits iron sequestration in tumor macrophages enhancing anti-tumor immunity

Current anti tumor immunotherapies are primarily centered around augmenting T cell responses. However, innate cells, a major constituent of tumor immune microenvironment, are instrumental in sustaining adaptive immune responses and thus could be exploited for upcoming immunotherapies. These cells being upstream in the immune pathway, provide a multifaceted immune response that includes the conservation of essential nutrients like iron. Gut commensals, which can incite innate immune activation via interaction with innate pattern recognition receptors, can be modulated for a favorable anti cancer therapy. However, the lack of effective paradigms to identify such bacteria and their mechanism of action is a bottleneck. Here we identify a food commensal bacterial strain Lactiplantibacillus plantarum IMB19 (LpIMB19), which augments anti tumor immunity in several syngeneic and orthotopic murine as well as1 human patient derived xenograft tumor models in mice. LpIMB19 treatment skews tumor infiltrating CD11b+F4/80+ macrophages to a classically activated inflammatory phenotype, which robustly induces interferon y producing cytotoxic CD8 T cells. Concurrently, it triggers nutritional immunity in activated macrophages, which deploy high affinity iron transporter Lipocalin 2 (LCN2) to capture trace iron from the microenvironment and switch to an iron sequestration phenotype. This iron deprivation extends to growing tumor cells, setting up a cycle of tumor cell death, epitope expansion, and subsequent tumor clearance, thereby complementing anti tumor immunity. Further, we isolated the effector component from the bacteria, a rhamnose rich heteropolysaccharide (RHP), primarily responsible for enhanced immune stimulation. Since diet associated commensal strains are restricted by geography and cultural traditions, our findings attest that such food commensals, long associated with the human gut, can be developed into oncobiotics by harnessing the ability of both innate and adaptive immune cells for a multi layered anti cancer immunity.