Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors (VAC10P.965)

• Published in: The Journal of immunology (1950) Vol. 192; no. 1_Supplement; pp. 204 - 204.4
• Main Authors: Soong, Rueyshyang, Wu, Tc, Hung, Chien-Fu
• Format: Journal Article
• Language: English
• Published: 01.05.2014
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.192.Supp.204.4

Abstract CD40 and CD40 ligand (CD40L) are costimulatory molecules that play a pivotal role in the proinflammatory immune response. Here, two tumor-associated antigen (TAA) animal models, a p53-based and a GP100-based model, were utilized to examine the ability of CD40-CD40L to improve antigen-specific CTL-mediated antitumor immune responses. Although p53 and GP100 are self-antigens that generate low affinity antigen-specific CD8+ T cells, studies have shown that their functional avidity can be improved with CD40L-expressing APCs. Therefore, in the current study, we immunized mice with a DNA construct encoding a TAA in conjunction with another encoding CD40L via intramuscular injection followed by electroporation. We observed a significant increase in the antigen-specific CTL-mediated immune responses and potent antitumor effects in both models. Antibody depletion experiments demonstrated that CD8+ T cells play a crucial role in eliciting antitumor effects in vaccinated mice. Furthermore, we showed that in vitro stimulation with irradiated tumor cells expressing both TAA and CD40L improved the avidity of antigen-specific CD8+ T cells. Thus, our data show that vaccination with a TAA/CD40L DNA can induce potent antitumor effects against TAA-expressing tumors through the generation of high avidity antigen-specific CD8+ T cells. Our study serves as an important foundation for future clinical translation.