Our data reveal that MDSCs provide a niche for pathogen survival and tailor immunity in TB. These findings suggest MDSCs as amenable targets for host-directed therapies and emphasize them as cellular-immune regulators during chronic inflammatory conditions, including chronic infections and microbial complications of neoplastic disorders.

Animal tumor models and human cancer studies have provided convergent evidence that chronic psychological stress plays a decisive role in modulating anti-tumor T cell immunity. However, whether chronic stress also affects anti-cancer vaccine strategies that rely on the induction of functional tumor-specific T cells has not been investigated yet. In this study we provide direct evidence that chronic stress suppresses the therapeutic efficacy of a biodegradable poly(d,l-lactide-co-glycolide) microsphere (PLGA-MS) based cancer vaccine in a murine melanoma model. Exposure of mice to social disruption stress (SDR), a well-established model mimicking psychological chronic stress in humans, significantly impaired tumor protection in response to cancer vaccination under both prophylactic and therapeutic conditions. Vaccine failure in stressed mice correlated with significantly reduced generation of interferon-γ (IFN-γ)-producing T effectors and CTL-mediated killing. Phenotypic analysis of dendritic cells (DCs) revealed that both migratory and lymphoid-resident DCs failed to undergo full maturation upon antigen uptake. Notably, decreased DC maturation was associated with a significant impairment of peripheral DCs to migrate to draining LNs and to prime subsequent T responses in vivo. In conclusion, chronic stress represents an important factor mediating immunosuppression in cancer-vaccinated hosts by impairing DC functions and subsequent T priming. Potentially, the mechanistic insights gained in this study open new avenues in utilizing the full potential of anti-cancer vaccination strategies.

Immunity in infection, inflammation and malignancy differs markedly in man and mouse. Still, we learn about human immunity in large extent from experimental mouse models. We propose a novel data integration approach which identifies concordant and discordant gene expression patterns of the immune responses in heterologous data sets. We have conducted experiments to compare human and murine transcriptional responses to Mycobacterium tuberculosis (Mtb) infection in whole blood (WB) as well as macrophages and compared them with simulated as well as publicly available data. Our results indicate profound differences between patterns of gene expression in innate and adaptive immunity in man and mouse upon Mtb infection. We characterized differential expression of T-cell related genes corresponding to the differences in phenotype between tuberculosis (TB) highly and low susceptible mouse strains. Our approach is general and facilitates the choice of optimal animal model for studies of the human immune response to a particular disease.

The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.

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