Activation of dendritic cells by a synthesized small molecule for breast cancer vaccination.

Abstract

e13149 Background: Dendritic cell-based vaccination is a promising immunotherapy for treating various types of cancer. However, tumor-loaded dendritic cells alone have limited treatment efficacy. We have designed a small molecule mimicking the action of damage-associated molecular pattern molecules as an adjuvant for activating dendritic cells in vitro, which demonstrated augmented treatment efficacy. Methods: We aimed at exploring the roles of the synthesized small molecule in augmenting the efficacy of dendritic cell-based cancer vaccination to target triple negative breast cancer. Breast cancer mouse model is constructed using a 4T1 tumor cell line. Data were analyzed using a two-tailed unpaired t-test. Results: Mouse dendritic cells could be activated in vitro by the small molecule as an adjuvant evidenced by increased expression of MHC-I, MHC-II and CD40. Augmented motility of dendritic cells was also observed after treatment with the adjuvant. The signaling of NFkB is remarkably activated in dendritic cells by the adjuvant, which facilitates the maturation of dendritic cells. Engraftment of adjuvant-primed dendritic cells loaded with 4T1 tumor antigen into 4T1 tumor-bearing mice efficiently reduced the tumor size and improved survival, compared with the group treated with dendritic cells only. After injection of adjuvant-activated dendritic cells, both CD4 T cell and CD8 T cell populations were expanded in the spleen and lymph nodes draining the tumor sites. Furthermore, the adjuvant could promote the production of IFN-γ and IL-2, cytokines required for T cell activation and expansion. Next, splenocytes were obtained from individual mice after dendritic cell-based treatment. Upon re-encounter with the tumor antigen in vitro, remarkable expansion of T cell populations with a memory cell feature was confirmed in splenocytes derived from mice that received adjuvant-treated dendritic cells. Consistently, production of TNF-α, IFN-γ and granzyme B, was profoundly increased in these T cells associated with the adjuvant treatment. Conclusions: Our work suggests a novel dendritic cell-based cancer immunotherapy by using a small molecule mimicking the action of damage-associated molecular pattern molecules, which have documented immune potentiation activities.