Nanoparticle based depletion of Myeloid-derived Suppressor cells in Tuberculosis

Abstract

Abstract The bacterial pathogen Mycobacterium tuberculosis (Mtb) successfully evades host innate immune responses to cause tuberculosis (TB) disease. Recent studies showed that myeloid-derived suppressor cells (MDSCs) are recruited to the lung after Mtb infection and harbor Mtb. While MDSC-mediated negative regulation of tumor micro-environments in cancer has been extensively studied, in-depth analyses of the phenotype, functions and transcriptional signatures of MDSCs in TB are lacking. In this study we sought to characterize MDSCs in the lungs of Mtb-infected mice and develop tools for depleting MDSCs as a strategy for host-directed therapy. We determined MDSCs in the aerosol mouse model of TB and in human blood using flow cytometry. MDSCs are recruited into the lung as early as 2 weeks post-infection and expresses immunomodulatory mediators associated with immune suppression such as iNOS, IDO and arginase. We recently reported the development of novel synthetic nanoparticle antibodies (SNAbs) that specifically target and deplete MDSCs via antibody-like mechanisms. We used SNAbs to deplete Mtb-induced MDSCs in vitro and in human PBMCs ex vivo. Interestingly, we found that SNAbs efficiently depleted MDSCs in both models. To test the efficacy of SNAb-mediated depletion of MDSCs in mouse lungs in vivo, we first used a murine lung cancer model and found that intra-tracheal delivery of SNAbs successfully depleted MDSCs in vivo. Ongoing studies include evaluating the ability of SNAbs to deplete lung MDSCs following Mtb infection of mice and to assess the impact on lung T cell functions, pathology and Mtb burden. These studies will establish a platform to investigate MDSCs as a target for host-directed therapies that improve TB treatment efficacy. Supported by grant from NIH (1R01AI155023-01A1)