Recombinant Cholera Toxin B Subunit Activates Dendritic Cells and Enhances Antitumor Immunity

Abstract

Activation of dendritic cells (DC) is crucial for priming of cytotoxic T lymphocytes (CTL), which have a critical role in tumor immunity, and it is considered that adjuvants are necessary for activation of DC and for enhancement of cellular immunity. In this study, we examined an adjuvant capacity of recombinant cholera toxin B subunit (rCTB), which is non‐toxic subunit of cholera toxin, on maturation of murine splenic DC. After the in vitro incubation of DC with rCTB, the expression of MHC class II and B7–2 on DC was upregulated and the secretion of IL‐12 from DC was enhanced. In addition, larger DC with longer dendrites were observed. These data suggest that rCTB induced DC maturation. Subsequently, we examined the induction of tumor immunity by rCTB‐treated DC by employing Meth A tumor cells in mice. Pretreatment with subcutaneous injection of rCTB‐treated DC pulsed with Meth A tumor lysate inhibited the growth of the tumor cells depending on the number of DC. Moreover, intratumoral injection of rCTB‐treated DC pulsed with tumor lysate had therapeutic effect against established Meth A tumor. Immunization with DC activated by rCTB and the tumor lysate increased number of CTL precursor recognizing Meth A tumor. The antitumor immune response was significantly inhibited in CD8+ T cell‐depleted mice, although substantial antitumor effect was observed in CD4+ T cell‐depleted mice. These results indicated that rCTB acts as an adjuvant to enhance antitumor immunity through DC maturation and that CD8+ T cells play a dominant role in the tumor immunity. Being considered to be safe, rCTB may be useful as an effective adjuvant to raise immunity for a tumor in clinical application.

Cholera toxin B subunit promotes the induction of regulatory T cells by preventing human dendritic cell maturation

“…These results are in agreement with a previous observation made in the murine system, whereby free CTB, differently from CTB conjugated with antigens, was found not to enhance the cell-surface levels of CD80 and CD86 [7]. However, they are in contrast with other data reporting the effect of CTB on splenic murine DC, which demonstrated that the in vitro incubation of murine DC with rCTB induces up-regulation of the expression of MHC class II and CD86 on DC and an increased secretion of IL-12 [29]. Reasons for these discrepancies are not easily recognized, but heterogeneity of myeloid murine DC and their state of maturation might account for the contrasting results observed in the murine system [30,31].…”

Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)–1/TIM4 interaction as a therapeutic strategy in a dendritic cell–induced peanut allergy model

“…We also observed that CT upregulated costimulatory molecules CD80 and CD86, and MHC II on DCs, in agreement with previous reports. 21 Thus, these PE antigen-loaded DCs would have acquired the capability to generate the necessary signals for PEspecific T H 2 cell activation.…”

Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice

“…CTB exhibits differential consequences in stimulated DCs or conjugation to antigens. It has been shown to significantly enhance the immunogenicity of linked exogenous antigens 12 through induction of DC activation, 13,14 enhanced B-cell and T-cell responses 15 , and decrease the dose of antigen. 12 Based on our previous studies, we found that the efficacy of immune responses induced by vaccine antigen depended on the level of inflammation or the strength of innate immunity induced by co-vaccinated adjuvants.…”