Mitochondrial metabolism is a tightly regulated process that plays a central role throughout the lifespan of hematopoietic cells. Herein, we analyze the consequences of the mitochondrial oxidative phosphorylation (OXPHOS)/metabolism disorder associated with the cell-specific hematopoietic ablation of apoptosis-inducing factor (AIF). AIF-null (AIF ) mice developed pancytopenia that was associated with hypocellular bone marrow (BM) and thymus atrophy. Although myeloid cells were relatively spared, the B-cell and erythroid lineages were altered with increased frequencies of precursor B cells, pro-erythroblasts I, and basophilic erythroblasts II. T-cell populations were dramatically reduced with a thymopoiesis blockade at a double negative (DN) immature state, with DN1 accumulation and delayed DN2/DN3 and DN3/DN4 transitions. In BM cells, the OXPHOS/metabolism dysfunction provoked by the loss of AIF was counterbalanced by the augmentation of the mitochondrial biogenesis and a shift towards anaerobic glycolysis. Nevertheless, in a caspase-independent process, the resulting excess of reactive oxygen species compromised the viability of the hematopoietic stem cells (HSC) and progenitors. This led to the progressive exhaustion of the HSC pool, a reduced capacity of the BM progenitors to differentiate into colonies in methylcellulose assays, and the absence of cell-autonomous HSC repopulating potential in vivo. In contrast to BM cells, AIF thymocytes compensated for the OXPHOS breakdown by enhancing fatty acid β-oxidation. By over-expressing CPT1, ACADL and PDK4, three key enzymes facilitating fatty acid β-oxidation (e.g., palmitic acid assimilation), the AIF thymocytes retrieved the ATP levels of the AIF cells. As a consequence, it was possible to significantly reestablish AIF thymopoiesis in vivo by feeding the animals with a high-fat diet complemented with an antioxidant. Overall, our data reveal that the mitochondrial signals regulated by AIF are critical to hematopoietic decision-making. Emerging as a link between mitochondrial metabolism and hematopoietic cell fate, AIF-mediated OXPHOS regulation represents a target for the development of new immunomodulatory therapeutics.

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Preclinical and clinical studies have shed light on the beneficial role of bacteria for cancer therapy. Indeed, these studies have demonstrated that these microorganisms have beneficial properties that allow them to selectively colonize tumor and that they could also be considered as predictive drug efficacy biomarkers. Based on these results, bacteria are now used for delivering therapeutic components or for shaping the gut microbiota. Ultimately these approaches lead to the activation of an immune response against the tumor. Owing to our scientific and technological expertise in manipulating microbes, we propose tailor-made strategies for investigating the efficacy of bacteria-based treatments and/or the effect of therapies on the microbiota both in vitro and in vivo. Different methods/analyses can be used for culturing, detecting, quantifying, identifying and localizing live bacteria (e.g. counting of CFUs, PMA-qPCR, 16 rRNA gene sequencing, mass spectrometry, bioluminescence) in simple or complex samples (e.g. from culture of single bacterial species to rodent/human stools or other tissues). In addition, a continuum of assays allows us to evaluate the impact of bacteria or derived products directly on tumor and/or immune cells (e.g. immune infiltrate and phenotyping, cytokine/chemokine profiling, tumor burden). We will highlight some results obtained in a cancer context such as the immunostimulatory properties of bacteria or their derivatives, the selective colonization of tumor tissue by bacteria, the benefits in delivery of therapeutic proteins or antigens by bacteria, the impact of tumor engraftment/growth on gut microbiota, the effects of chemotherapeutic agents on intestinal microflora, the consequences of supplementation with bacteria or antibiotics treatment on the response to immune checkpoint inhibitors. Altogether these data demonstrate that bacteria are now allies in the treatment of cancer and that our comprehensive platform is suitable for evaluating both in vitro and in vivo therapeutics developed from bacteria (individuals, consortium or derived products; native or modified). All these technologies can be also applied to develop novel therapeutic strategies for inflammatory and infectious diseases known to increase the risk of cancer development. Citation Format: Sylvie Maubant, Marie Leblanc, Elisabeth Bertrand, Audrey Bertaux, Loic Morgand, Maxime Ramelet, Marie Lux, Olivier Duchamp, Fabrice Vivani. Using individual or a consortium of bacteria for immuno-oncology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3053.