Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis

Abstract

Despite recent advances in tuberculosis (TB) drug development and availability, successful antibiotic treatment is challenged by the parallel development of antimicrobial resistance. As a result, new approaches toward improving TB treatment have been proposed in an attempt to reduce the high TB morbidity and mortality rates. Host-directed therapies (HDTs), designed to modulate host immune components, provide an alternative approach for improving treatment outcome in both non-communicable and infectious diseases. Many candidate immunotherapeutics, designed to target regulatory myeloid immune components in cancer, have so far proven to be of value as repurposed HDT in TB. Several of these studies do however lack detailed description of the mechanism or host pathway affected by TB HDT treatment. In this review, we present an argument for greater appreciation of the role of regulatory myeloid cells, such as myeloid-derived suppressor cells (MDSC), as potential targets for the development of candidate TB HDT compounds. We discuss the role of MDSC in the context of Mycobacterium tuberculosis infection and disease, focussing primarily on their specific cellular functions and highlight the impact of HDTs on MDSC frequency and function.

The Emerging Role of Myeloid-Derived Suppressor Cells in Tuberculosis

“…Shortly after identification of MDSC in TB patients and murine models, these cells emerged as promising targets for adjunct host-directed therapy (HDT) approaches (8, 41, 71). The focus of such strategies has been to reverse the impact of MDSC on T-cell immunity in TB by implementing host modulating therapeutic strategies such as those blocking MDSC induction or activation, inhibiting MDSC function or reversing their suppressive function.…”

“…The focus of such strategies has been to reverse the impact of MDSC on T-cell immunity in TB by implementing host modulating therapeutic strategies such as those blocking MDSC induction or activation, inhibiting MDSC function or reversing their suppressive function. These strategies have been recently reviewed elsewhere (71). More recently, denileukin diftitox, an anti-neoplastic agent comprised of IL-2 and Diphtheria toxin, potentiates standard TB treatment in a mouse model through the elimination of MDSC and Treg (72).…”

“…Although not yet tested in TB, a combination treatment of IL-17R and IFN-γ has shown potential in cancer, by reducing the levels of MDSC and increasing T-cells (76). Other MDSC targeting agents tested in cancer, which have shown potential in TB, but with unknown effects on MDSC, include metformin, tyrosine kinase inhibitors (imatinib), PDE-5 inhibitors, and arginase inhibitors (71). The COX-2 inhibitor, etoricoxib, is currently evaluated as HDT for TB and its effect on MDSC levels will be considered in the trial (NCT02503839).…”

Drug resistance profiles and trends in drug-resistant tuberculosis at a major hospital in Guizhou Province of China

“…In order to ensure cure without relapse, reduce the high TB mortality rate and prevent the spread of drug-resistant TB, especially MDR-TB, new therapeutic approaches toward improving TB treatment outcomes were summarized in two recent review articles 19,20. These new approaches included discovery of new chemical entity with a novel mechanism of action, repurposing of old drugs, the use of novel drug delivery systems and development of host-directed therapies.…”

Interrogating Fractionation and Other Sources of Variability in Shotgun Proteomes Using Quality Metrics

“…[4,5] These cells have therefore been identified as potential targets in immunotherapeutic strategies. [6,7] Although sufficient quantities of MDSCs can be obtained from tissue in mice and blood in humans, subsequent analysis steps can affect the populations of enriched MDSCs; both mechanical and enzymatic purification processes as well as isolation techniques or cryopreservation can introduce variability. Furthermore, MDSCs require gentle handling and cool temperatures to avoid interfering with measurement of their biological and functional properties.…”