Efficient induction of a Her2-specific anti-tumor response by dendritic cells pulsed with a Hsp70L1–Her2_(341–456) fusion protein

摘要

Heat shock proteins(HSPs)have been shown to interact with antigen-presenting cells(APCs),especially dendritic cells(DCs).HSPs act as potent adjuvants,inducing a Th1 response,as well as antigen-specific CD8^(+) cytotoxic T lymphocytes(CTL)via cross-presentation.Our previous work has demonstrated that Hsp70-like protein 1(Hsp70L1),a new member of the Hsp70 subfamily,can act as a powerful Th1 adjuvant in a DC-based vaccine.Here we report the efficient induction of tumor antigen-specific T cell immune response by DCs pulsed with recombinant fusion protein of Hsp70L1 and Her2_(341–456),the latter of which is a fragment of Her2/neu(Her2)containing E75(a HLA-A2 restricted CTL epitope).The fusion protein Hsp70L1–Her2_(341–456) promotes the maturation of DCs and activates them to produce cytokines,such as IL-12 and TNF-a,and chemokines,such as MIP-1a,MIP-1b and RANTES.Taken together,these results indicate that the adjuvant activity of Hsp70L1 is maintained in the fusion protein.Her2-specific HLA-A2.1-restricted CD8^(+) CTLs can be generated efficiently either from the Peripheral blood lymphocytes(PBL)of healthy donors or from the splenocytes of immunized HLA-A2.1/K^(b) transgenic mice by in vitro stimulation or immunization with DCs pulsed with the Hsp70L1–Her2_(341–456) fusion protein.This results in more potent target cell killing in an antigen-specific and HLA-A2.1-restricted manner.Adoptive transfer of splenocytes from transgenic mice immunized with Hsp70L1–Her2_(341–456)-pulsed DCs can markedly inhibit tumor growth and prolong the survival of nude mice with Her2^(+)/HLA-A2.1^(+) human carcinomas.These results suggest that Hsp70L1–Her2_(341–456)-pulsed DCs could be a new therapeutic vaccine for patients with Her2^(+) cancer.