Govaerts, J. | bioRxiv Science

bioRxiv2024

Chimeric aggregative multicellularity in absence of kin discrimination

Aggregative multicellularity is a cooperative strategy employed by some microorganisms. Unlike clonal expansion within protected environments during multicellular eukaryotic development, an aggregation strategy introduces the potential for genetic conflicts and exploitation by cheaters, threatening the stability of the social system. Myxococcus xanthus, a soil-dwelling bacterium, employs aggregative multicellularity to form multicellular fruiting bodies that produce spores in response to starvation. Studies of natural fruiting bodies show that this process is restricted to close kin or clonemates. Here, we investigate the mechanisms underlying kin recognition during development in M. xanthus. By co-culturing two distantly related M. xanthus strains under vegetative and starvation conditions, we observed that the strains segregate in both contexts. During vegetative growth, one strain antagonized the other using the type VI secretion system (T6SS). T6SS-mediated antagonism was also observed during development, resulting in monoclonal fruiting bodies when WT strains were mixed. In contrast, mixtures of T6SS knockout strains formed chimeric fruiting bodies, that produced viable spores from both strains. These findings suggest that T6SS is the primary mechanism of kin discrimination in distantly related M. xanthus strains, and its use ensures the development of monoclonal fruiting bodies and social integrity.

microbiology↗

bioRxiv2023

A lymph node-to-tumour PD-L1+macrophage circuit antagonizes dendritic cell immunotherapy

Immune-checkpoint blockers (ICB) provide limited benefit against T cell-depleted tumours, calling for therapeutic innovation. Here, we aimed at designing a new type of dendritic cell (DC) vaccine by unbiased computational integration of multi-omics data from cancer patients. In a first attempt, a DC vaccine designed to present tumor antigens from cancer cells succumbing to immunogenic cancer cell death (ICD) and to elicit high type I interferon (IFN) responses failed to induce the regression of mouse tumors lacking T cell infiltrates. In lymph nodes (LNs), instead of activating CD4+ and CD8+T cells, DCs stimulated immunosuppressive PD-L1+LN-associated macrophages (LAMs) via a type I IFN response. Moreover, DC vaccines of this type stimulated pre-existing, T cell-suppressive, PD-L1+tumour-associated macrophages (TAMs). This created a T cell-suppressive circuit of PD-L1+macrophages, spanning across LNs and tumours. Accordingly, DC vaccines synergised with PD-L1 blockade to deplete PD-L1+macrophages, suppress myeloid inflammation affecting the tumor bed and draining lymph nodes, and de-inhibit effector/stem-like memory T cells, eventually causing tumour regression. The synergistic interaction between the DC vaccine and PD-L1 blockade was lost when DCs were manipulated to lose Ifnar1or Ccr7 or when macrophages were depleted. Interestingly, clinical DC vaccines also potentiated lymphocyte-suppressive PD-L1+TAMs in patients bearing T cell-depleted tumours. Altogether, our results reveal the existence of a novel PD-L1+LAM/TAM-driven immunosuppressive pathway that can be elicited by DC vaccines, yet can be subverted for improving the outcome of immunotherapy.

immunology↗