Dataset Information

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.

SUBMITTER: du Plessis N

PROVIDER: S-EPMC6160538 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis.

du Plessis Nelita N Kotze Leigh A LA Leukes Vinzeigh V Walzl Gerhard G

Frontiers in cellular and infection microbiology 20180921

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 inf ...[more]

PMID: 30298121

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Project description:Glioblastoma (GBM) is the most common malignant primary brain tumor. Glioblastomas contain a large non-cancerous stromal compartment including various populations of tumor-associated macrophages and other myeloid cells, of which the presence was documented to correlate with malignancy and reduced survival. Via single-cell RNA sequencing of human GBM samples, only very low expression of PD-1, PD-L1 or PD-L2 could be detected, whereas the tumor micro-environment featured a marked expression of signal regulatory protein alpha (SIRPα), an inhibitory receptor present on myeloid cells, as well as its widely distributed counter-receptor CD47. CITE-Seq revealed that both SIRPα RNA and protein are prominently expressed on various populations of myeloid cells in GBM tumors, including both microglia- and monocyte-derived tumor-associated macrophages (TAMs). Similar findings were obtained in the mouse orthotopic GL261 GBM model, indicating that SIRPα is a potential target on GBM TAMs in mouse and human. A set of nanobodies, single-domain antibody fragments derived from camelid heavy chain-only antibodies, was generated against recombinant SIRPα and characterized in terms of affinity for the recombinant antigen and binding specificity on cells. Three selected nanobodies binding to mouse SIRPα were radiolabeled with 99mTc, injected in GL261 tumor-bearing mice and their biodistribution was evaluated using SPECT/CT imaging and radioactivity detection in dissected organs. Among these, Nb15 showed clear accumulation in peripheral organs such as spleen and liver, as well as a clear tumor uptake in comparison to a control non-targeting nanobody. A bivalent construct of Nb15 exhibited an increased accumulation in highly vascularized organs that express the target, such as spleen and liver, as compared to the monovalent format. However, penetration into the GL261 brain tumor fell back to levels detected with a non-targeting control nanobody. These results highlight the tumor penetration advantages of the small monovalent nanobody format and provide a qualitative proof-of-concept for using SIRPα-targeting nanobodies to noninvasively image myeloid cells in intracranial GBM tumors with high signal-to-noise ratios, even without blood-brain barrier permeabilization.

Dataset Information

Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis.

Publications

Translational Potential of Therapeutics Targeting Regulatory Myeloid Cells in Tuberculosis.

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