Abstract
Immunotherapy against cancer and infectious disease holds the promise of high efficacy with minor side effects. Mucosal vaccines to protect against tumors or infections disease agents that affect the upper airways or the lung are still lacking, however. One mucosal vaccine candidate is the B-subunit of Shiga toxin, STxB. In this review, we compare STxB to other immunotherapy vectors. STxB is a non-toxic protein that binds to a glycosylated lipid, termed globotriaosylceramide (Gb3), which is preferentially expressed by dendritic cells. We review the use of STxB for the cross-presentation of tumor or viral antigens in a MHC class I-restricted manner to induce humoral immunity against these antigens in addition to polyfunctional and persistent CD4+ and CD8+ T lymphocytes capable of protecting against viral infection or tumor growth. Other literature will be summarized that documents a powerful induction of mucosal IgA and resident memory CD8+ T cells against mucosal tumors specifically when STxB-antigen conjugates are administered via the nasal route. It will also be pointed out how STxB-based vaccines have been shown in preclinical cancer models to synergize with other therapeutic modalities (immune checkpoint inhibitors, anti-angiogenic therapy, radiotherapy). Finally, we will discuss how molecular aspects such as low immunogenicity, cross-species conservation of Gb3 expression, and lack of toxicity contribute to the competitive positioning of STxB among the different DC targeting approaches. STxB thereby appears as an original and innovative tool for the development of mucosal vaccines in infectious diseases and cancer.
Highlights
Shiga Toxin and Its Intracellular TraffickingThe bacterial Shiga toxin belongs to the family of AB5 toxins [1]. These are composed of a catalytic A-subunit and a homopentameric B-subunit which is made from five identical B-fragments
Key Contribution: STxB is a vector for the delivery of antigenic peptides and proteins to dendritic cells
This leads to cell death and contributes to the overall pathology that is associated with Shiga toxin producing enterohemorrhagic Escherichia coli bacteria, which bring about hemolytic-uremic syndrome, the leading cause of pediatric renal failure [5,6], but which poses health risks to adults [7]
Summary
The bacterial Shiga toxin belongs to the family of AB5 toxins [1]. These are composed of a catalytic A-subunit and a homopentameric B-subunit which is made from five identical B-fragments. The B-subunits of AB5 toxins bind to glycans of cellular protein or lipids [2]. STxB is needed for toxin binding to cells, and for the trafficking of the catalytic A-subunits inside the cells [4] (Figure 1). With the help of STxB, the A-subunit of Shiga toxin is delivered into the cytosol where it inhibits protein biosynthesis by modifying ribosomal RNA. This leads to cell death and contributes to the overall pathology that is associated with Shiga toxin producing enterohemorrhagic Escherichia coli bacteria, which bring about hemolytic-uremic syndrome, the leading cause of pediatric renal failure [5,6], but which poses health risks to adults [7]. The catalytic A-subunit is translocated to the cytosol using the cellular retrotranslocation machinery [25]
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