DC-based tumor vaccine research has largely focused on enhancing DC maturation/costimulation and antigen presentation in order to break tolerance against self tumor-associated antigens. DC immunization can activate autoreactive T cells but rarely causes autoimmune pathologies, indicating that self tolerance at the host level is still maintained in the vaccinated hosts. This study in mice reveals a novel regulatory mechanism for the control of self tolerance at the host level by DCs through the restriction of positive cytokine feedback loops by cytokine signaling inhibitor SOCS1. The study further finds the requirement of persistent antigen presentation by DCs for inducing pathological autoimmune responses against normal tissues and tumor, which can be achieved by silencing SOCS1 to unleash the unbridled signaling of IL-12 and the downstream cytokine cascade. However, the use of higher-affinity self peptides, enhancement of DC maturation, and persistent stimulation with cytokines or TLR agonists fail to break tolerance and induce pathological antitumor immunity. Thus, this study indicates the necessity of inhibiting SOCS1, an antigen presentation attenuator, to break self tolerance and induce effective antitumor responses.
Kevin Evel-Kabler, Xiao-Tong Song, Melissa Aldrich, Xue F. Huang, Si-Yi Chen
Title and authors | Publication | Year |
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Immunological research using RNA interference technology
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Immunosuppressive Strategies that are Mediated by Tumor Cells
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Annual Review of Immunology | 2007 |
Autoimmunity stimulated by adoptively transferred dendritic cells is initiated by both alphabeta and gammadelta T cells but does not require MyD88 signaling.
Martin DA, Zhang K, Kenkel J, Hughes G, Clark E, Davidson A, Elkon KB |
Journal of immunology (Baltimore, Md. : 1950) | 2007 |
Regression of intestinal adenomas by vaccination with heat shock protein 105‐pulsed bone marrow‐derived dendritic cells in Apc Min/+ mice
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Cancer Science | 2007 |