Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans

May 3, 2011Blood

Different ways particle and dissolved yeast sugars control natural and learned cancer-fighting immune responses

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Abstract

Orally administered yeast-derived particulate β-glucan significantly delayed tumor progression and activated immune responses.

Yeast-derived particulate β-glucan activated dendritic cells and macrophages through the dectin-1 receptor pathway.
Activated dendritic cells promoted the priming and differentiation of Th1 cells and cytotoxic T-lymphocytes in vitro.
Deficiency of the dectin-1 receptor completely eliminated the antitumor effects associated with particulate β-glucan.
In contrast, yeast-derived soluble β-glucan did not activate dendritic cells and had no therapeutic effect on its own.
Soluble β-glucan significantly enhanced the effectiveness of antitumor monoclonal antibodies via a complement activation pathway, independent of the dectin-1 receptor.

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β-glucans have been reported to function as a potent adjuvant to stimulate innate and adaptive immune responses. However, β-glucans from different sources are differential in their structure, conformation, and thus biologic activity. Different preparations of β-glucans, soluble versus particulate, further complicate their mechanism of action. Here we show that yeast-derived particulate β-glucan activated dendritic cells (DCs) and macrophages via a C-type lectin receptor dectin-1 pathway. Activated DCs by particulate β-glucan promoted Th1 and cytotoxic T-lymphocyte priming and differentiation in vitro. Treatment of orally administered yeast-derived particulate β-glucan elicited potent antitumor immune responses and drastically down-regulated immunosuppressive cells, leading to the delayed tumor progression. Deficiency of the dectin-1 receptor completely abrogated particulate β-glucan-mediated antitumor effects. In contrast, yeast-derived soluble β-glucan bound to DCs and macrophages independent of the dectin-1 receptor and did not activate DCs. Soluble β-glucan alone had no therapeutic effect but significantly augmented antitumor monoclonal antibody-mediated therapeutic efficacy via a complement activation pathway but independent of dectin-1 receptor. These findings reveal the importance of different preparations of β-glucans in the adjuvant therapy and allow for the rational design of immunotherapeutic protocols usable in clinical trials.

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Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived β-glucans

Abstract

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