Dušan Radojević1*, Marina Bekić2, Sergej Tomić2 and Jelena Đokić1
1Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia
2Institute for the Application of Nuclear Energy, University of Belgrade, Serbia
dusan.radojevic [at] imgge.bg.ac.rs
Abstract
Immune-mediated diseases, including cancer and autoimmune disorders, represent a growing global health burden. Although immune checkpoint inhibitors and immunogenic cell-based therapies achieved substantial success in oncology, immunosuppressive cell therapies are increasingly investigated for autoimmune diseases. Accumulating evidence identified the gut microbiota as an important factor influencing immunotherapy efficacy and immune-related adverse effects. We therefore investigated how gut microbiota profiles correlate with cell-based immunotherapies in two models.
In healthy human donors, we profiled fecal microbial communities and identified taxa associated with distinct dendritic cell (DC) phenotypes. Donors with higher microbial diversity and abundant short-chain-fatty-acid-producing bacteria generated monocyte-derived DCs with a regulatory phenotype characterized by high ILT-3 expression, low CD1a expression, and weaker maturation potential. In contrast, donors enriched in Bifidobacterium and Collinsella produced DCs with increased CD1a expression, upregulated co-stimulatory molecules (CD40, CD86), and enhanced pro-inflammatory cytokine responses, including TNF-α, IL-6, IL-8, and IL-12. These findings indicated that specific gut microbiota configurations may promote differentiation of highly immunogenic DCs and potentially improve the efficacy of DC-based anticancer vaccines. We further evaluated microbiota-associated effects of immunosuppressive therapy in a rat model of experimental autoimmune encephalomyelitis (EAE). Untreated EAE animals developed gut-barrier disruption, reduced microbial diversity, and pronounced alterations in microbial community structure. In contrast, treatment with bone-marrow-derived myeloid-derived suppressor cells (MDSCs), particularly following PGE₂ conditioning, preserved microbial diversity and maintained a microbiota profile associated with immunosuppressive metabolic functions. These changes were accompanied by expansion of IL-10-producing regulatory T and B cell populations and suppression of pathogenic Th1/Th17 immune responses, resulting in attenuation of disease severity.
Together, these findings demonstrated that specific gut microbiota configurations were closely associated with immune-cell immunogenicity and therapeutic responsiveness. The results highlighted the translational potential of microbiota-informed strategies and suggested that interventions based on probiotics, dietary fibres, and faecal microbiota transplantation could improve the efficacy of anticancer and anti-inflammatory immunotherapies.
Keywords: /
Acknowledgement: This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia, and by the Science Fund of the Republic of Serbia, PROMIS, #6062673, Nano-MDSC-Thera project.