Bacteria-triggered tumor-specific thrombosis to enable potent photothermal immunotherapy of cancer.
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ABSTRACT:
SUBMITTER: Yi X
PROVIDER: S-EPMC7428325 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Bacteria-based cancer immunotherapy, dated back to Coley’s toxins (inactivated bacteria) in 1893, has recently regained substantial attentions, usually by using attenuated bacteria to transform immune-silent “cold” tumors into immune-inflamed “hot” ones. However, while inactivated bacteria showed limited antitumor efficacy, attenuated live bacteria often possessed significant safety risks. Herein, by biomineralizing growth of manganese dioxide on the surface of paraformaldehyde-fixed gram-negative Salmonella typhimurium (S. typhimurium), we obtained MnO2-coated fixed S. typhimurium (M@F.S), which showed potent immune-stimulating effects via activating multiple pathways including Toll-like receptors (TLRs), cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Single intratumoral administration of M@F.S at safe doses resulted in surprisingly strong efficacies in suppressing various types of mouse tumor models and a rabbit cancer model, and the cured mice and rabbits gained immune memory to reject re-challenged tumors. An abscopal antitumor effect was also observed, suggesting systemic antitumor immunity triggered by local injection of M@F.S. The antitumor mechanisms of M@F.S were preliminarily demonstrated to be innate immune activation initiated by multiple signaling pathways, followed by subsequent activation of tumor-specific immune responses, together with the modulation of immunosuppressive tumor microenvironment. We further demonstrated the efficacy of biomineralized bacteria in inhibiting an orthotopic breast tumor model established on tree shrews, an alternative animal model to primates with better clinical relevance. Such oncolytic biomineralized bacteria could be a potent yet safe immunotherapeutic agent for treatment of various solid tumors.
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Project description:The crosstalk between the oral microbiome and oral cancer has yet to be characterized. This study recruited 218 patients for clinicopathological data analysis. Multiple types of specimens were collected from 27 patients for 16S rRNA gene sequencing, including 26 saliva, 16 swabs from the surface of tumor tissues, 16 adjacent normal tissues, 22 tumor outer tissue, 22 tumor inner tissues, and 10 lymph nodes. Clinicopathological data showed that the pathogenic bacteria could be frequently detected in the oral cavity of oral cancer patients, which was positively related to diabetes, later T stage of the tumor, and the presence of cervical lymphatic metastasis. Sequencing data revealed that compared with adjacent normal tissues, the microbiome of outer tumor tissues had a greater alpha diversity, with a larger proportion of Fusobacterium, Prevotella, and Porphyromonas, while a smaller proportion of Streptococcus. The space-specific microbiome, comparing outer tumor tissues with inner tumor tissues, suggested minor differences in diversity. However, Fusobacterium, Neisseria, Porphyromonas, and Alloprevotella were more abundant in outer tumor tissues, while Prevotella, Selenomonas, and Parvimonas were enriched in inner tumor tissues. Clinicopathology-specific microbiome analysis found that the diversity was markedly different between negative and positive extranodal extensions, whereas the diversity between different T-stages and N-stages was slightly different. Gemella and Bacillales were enriched in T1/T2-stage patients and the non-lymphatic metastasis group, while Spirochaetae and Flavobacteriia were enriched in the extranodal extension negative group. Taken together, high-throughput DNA sequencing in combination with clinicopathological features facilitated us to characterize special patterns of oral tumor microbiome in different disease developmental stages.
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