Targeting of myeloid-derived suppressor cells by all-trans retinoic acid as host-directed therapy for human tuberculosis

Abstract

Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.

Myeloid-Derived Suppressor Cells Mediate T Cell Dysfunction in Nonhuman Primate TB Granulomas

“…Apart from cancer, transplantation, and inflammatory pathologies, where these cells are extensively studied ( 12 – 15 ), MDSCs have been recently reported to be abundant in the blood ( 7 , 23 , 24 ), pleural effusions ( 7 ), and bronchoalveolar lavage (BAL) fluid ( 23 ) of active TB (ATB) patients. MDSCs could potently impair adaptive immunity by killing DCs ( 25 ) or inhibiting T cell functions ( 7 , 9 , 10 , 22 , 25 – 35 ).…”

“…Myelopoiesis-promoting growth factors, such as granulocyte colony-stimulating factor (G-CSF) ( 37 , 38 ), macrophage CSF (M-CSF), and granulocyte-macrophage CSF (GMCSF) ( 39 ), act together with inflammatory cytokines to promote MDSC expansion and to prevent their differentiation into terminally differentiated DCs, macrophages, or granulocytes ( 39 ). MDSCs potently suppress the function of both CD4 and CD8 T cells ( 10 , 22 , 25 – 33 , 35 , 36 ). Adoptive transferred MDSCs can induce antigen-specific CD8 T cell tolerance in mice ( 40 ).…”

“…Compared with other tolerogenic myeloid cells (e.g., regulatory DCs or regulatory macrophages) ( 12 – 15 ), MDSCs are unique in that they can be activated to suppress immunity by inflammatory signals ( 7 , 8 , 11 , 25 , 30 , 32 ). These include proinflammatory cytokines that are elevated after surgery and Toll-like receptor ligands, making MDSCs potentially well suited for targeting by adjunctive immunotherapeutics ( 11 , 25 , 30 , 32 , 34 , 35 , 41 ). MDSCs have recently received attention as potential targets for anti-TB immunotherapy ( 11 , 25 , 30 , 32 , 34 , 35 , 41 ).…”

“…These include proinflammatory cytokines that are elevated after surgery and Toll-like receptor ligands, making MDSCs potentially well suited for targeting by adjunctive immunotherapeutics ( 11 , 25 , 30 , 32 , 34 , 35 , 41 ). MDSCs have recently received attention as potential targets for anti-TB immunotherapy ( 11 , 25 , 30 , 32 , 34 , 35 , 41 ).…”

“…Our results raise the possibility that MDSCs can serve as a promising biomarker for ATB, while their disappearance could correlate with successful therapy ( 7 – 9 , 11 , 30 , 33 ). Furthermore, they may serve as a potential target for adjunctive TB therapeutics ( 9 , 11 , 25 , 30 , 32 , 35 , 36 , 41 ), helping to resolve the granulomatous TB niche and consequently the potential for reactivation from latent TB to ATB.…”