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Pore-forming toxin alpha-hemolysin efficiently improve the immunogenicity and protective efficacy of protein antigens by increasing antigen uptake and targeting ADAM10

ABSTRACT: Highly immunogenic exotoxins were proved to be efficient in improving the immunogenicity of polysaccharides, traditionally known as carrier proteins. However, the efficacy of exotoxins on protein antigens remains to be excluded. In the current study, the candidate antigen PA0833 from Pseudomonas aeruginosa was fused to the α-hemolysin mutant HlaH35A from Staphylococcus aureus. After immunization with the fusion protein, increased titers of PA0833-specific antibodies and higher protective efficacy were observed, companied with decreased bacterial burden and pro-inflammatory cytokines secretion when compared with PA0833 immunization alone. Then, by using fluorescently labeled antigens to track antigen uptake and delivery, we found that fusion to HlaH35A significantly improved antigen uptake in injected muscles and antigen delivery to draining lymph nodes. Both in vivo and in vitro studies demonstrated that increased antigen uptake by fusion to HlaH35A were mainly mediated by monocytes and macrophages in a macropinocytosis dependent manner, probably due to targeting ADAM10, the host receptor of Hla. Further, transcriptome analysis was performed and the result showed that several immune signaling pathways were activated by HPF, which also shed light on the mechanism of improved immunogenicity. Finally, improvement of immunogenicity by fusion to HlaH35A was also confirmed in two other anigens, GlnH from Klebsiella pneumoniae and the model antigen OVA, which indicated that HlaH35A could serve as a universal carrier protein to improve the immunogenicity of protein antigens.

ORGANISM(S): Mus musculus

PROVIDER: GSE167077 | GEO | 2021/02/20

REPOSITORIES: GEO

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Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

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Pore-forming toxin alpha-hemolysin efficiently improve the immunogenicity and protective efficacy of protein antigens by increasing antigen uptake and targeting ADAM10

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