Antitumor activity of peptides derived from immunoglobulins exerted in vivo involving dendritic cells and TGF-beta family protein signaling

Abstract

Previous results have demonstrated that peptides derived from CDRs immunoglobulins exhibit activity in vitro and in vivo against human cancer cell lines and against murine melanoma B16F10-Nex2 in syngeneic model C57BI6 H-2b mice. (Arruda et al, 2012; Dobroff et al., 2010). Anti-tumor effects observed after intraperitoneal injection of peptides could be reproduced using syngeneic dendritic cells primed with tumoral antigens and ex-vivo cells with peptides previously its adoptive transference in mice developing tumors. (Massaoka et al., 2013). These results indicated that in vivo antitumor peptides were readily incorporated into dendritic cells to induce an effective immune cellular response. DCs transferred as vaccines or isolated from cancer patients are influenced by tumors to take a suppressor phenotype with production of TGF-beta and production and induction of FOXP3 T reg cells, it seems evident that peptides that exert protective activity in vivo stimulate DCs take subtypes that lead to a Th1 protective response. Peptides can induce the formation of NO, production of pro-inflammatory cytokines IL-12, IL-6 and IFN gamma and co-stimulatory molecules. Anti-tumor agents activated dendritic cells through the TGF-beta and NO and IL-6 signaling. (Lee et al., 2011). A hypothesis to be investigated is that this signaling is induced by these factors and peptides involved include other mediators such as other TGF-beta proteins family and BMPs. Preliminary results indicate that several CDRs peptides with protective activity has affinity for BMP-2, 4 and 7 and other members of this family are expressed strongly on DCs, some regularly accumulating in the nucleus. Interaction of peptides with BMPs in the event could be a penetration, mechanism of endocytosis and/or a signaling pathway to be investigated on DCs.