Refine
Document Type
- Article (2)
Language
- English (2) (remove)
Has Fulltext
- yes (2)
Is part of the Bibliography
- no (2)
Keywords
- myeloid-derived suppressor cells (2) (remove)
Institute
Publisher
- Frontiers Media S.A. (1)
- MDPI (1)
Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection.
Treatment of high-risk neuroblastoma (NB) patients with the anti-GD2 antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.