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Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion.

ABSTRACT: The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont Fusobacterium nucleatum influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like Porphyromonas gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in iNKT cells, subsequently influencing the composition of mononuclear-phagocyte cells within the tumor microenvironment. Mechanistically, in vivo and in vitro experiments showed that P. gingivalis reduces the cytotoxic functions of iNKT cells, hampering the iNKT cell lytic machinery through increased expression of chitinase 3-like-1 protein (CHI3L1). Neutralization of CHI3L1 effectively restores iNKT cell cytotoxic functions suggesting a therapeutic potential to reactivate iNKT cell-mediated antitumour immunity. In conclusion, our data demonstrate how P. gingivalis accelerates CRC progression by inducing the upregulation of CHI3L1 in iNKT cells, thus impairing their cytotoxic functions and promoting host tumor immune evasion.

SUBMITTER: Diaz-Basabe A

PROVIDER: S-EPMC11321422 | biostudies-literature | 2024 Jan-Dec

REPOSITORIES: biostudies-literature

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Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion.

Díaz-Basabe Angélica A Lattanzi Georgia G Perillo Federica F Amoroso Chiara C Baeri Alberto A Farini Andrea A Torrente Yvan Y Penna Giuseppe G Rescigno Maria M Ghidini Michele M Cassinotti Elisa E Baldari Ludovica L Boni Luigi L Vecchi Maurizio M Caprioli Flavio F Facciotti Federica F Strati Francesco F

Gut microbes 20240101 1

The interaction between the gut microbiota and invariant Natural Killer T (iNKT) cells plays a pivotal role in colorectal cancer (CRC). The pathobiont Fusobacterium nucleatum influences the anti-tumor functions of CRC-infiltrating iNKT cells. However, the impact of other bacteria associated with CRC, like Porphyromonas gingivalis, on their activation status remains unexplored. In this study, we demonstrate that mucosa-associated P. gingivalis induces a protumour phenotype in ...[more]

PMID: 39132842

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Project description:Porphyromonas gingivalis (Pg) is a keystone pathogen in periodontitis, a highly prevalent disease manifested by chronic inflammation of the periodontium, alveolar bone resorption and tooth loss. During periodontitis pathobionts such as Pg can enter the bloodstream and growing evidence correlates periodontitis with increased risk of cardiovascular and neurodegenerative diseases. However, the mechanism by which immune cells respond to Pg challenge in vivo remains elusive. Pg produce aggressive proteolytic virulence factors termed gingipains which not only provide nutrients necessary for bacterial growth, but also subvert the host immune response, facilitating bacterial survival. Using transgenic zebrafish with fluorescently labelled macrophages and neutrophils, the role of gingipains in bacterial survival and interaction with phagocytes during systemic and local infection was examined. In contrast to the wild-type (W83) Pg, isogenic gingipain-null (ΔK/R-ab) or wild-type Pg treated with gingipain inhibitors caused less zebrafish mortality, bacteria were rapidly phagocytosed, acidified in phagosomes and eradicated when systemically injected, showing that gingipains are instrumental in preventing phagocytosis and intracellular killing of Pg by innate immune cells. Moreover, Pg were predominantly phagocytosed by macrophages, and gingipain depletion/inactivation increased bacterial phagocytosis when bacteria were injected either systemically or locally in the otic vesicle, with less bacteria internalised by neutrophils. This phenomenon was Pg-specific as Fusobacterium nucleatum caused neutrophil recruitment that then effectively phagocytosed these bacteria. These data demonstrate the important role of phagocytes, especially macrophages, in combating Pg infection and highlight the crucial protective role of gingipains in subverting the innate immune response. This study also emphasizes the advantages of using zebrafish to study interactions of Pg with phagocytes in vivo in real-time, providing a valuable experimental system for testing new therapeutic strategies aimed at reducing periodontal-associated systemic or neurodegenerative disease.

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Porphyromonas gingivalis fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion.

Publications

<i>Porphyromonas gingivalis</i> fuels colorectal cancer through CHI3L1-mediated iNKT cell-driven immune evasion.

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