Study Of Soluble PD1-based DNA Vaccine Targeting MUC1 VNTR And Survivin

Cancer is considered as a life-threatening disease in humans.Each year,millions of people died from cancer all over the world.Recently,the tumor immunotherapy has been heralded a breakthrough in clinical trials,and the most significant progress has been made in the immune checkpoint blockade therapy.Drugs targeting immune checkpoint receptors such as CTLA-4,PD-1 and PD-L1 are quite different from those of traditional tumor-targeting chemotherapies.Programmed cell death-1(PD-1)/programmed death ligand-1(PD-L1)interaction is one of the most important negative co-stimulatory signals that regulate multifunctional T cells activation.Till now,monoclonal antibodies have been developed to competitively inhibit the PD-1/PD-L1 pathway.However,anti-PD-1 is not the only form blocking immune checkpoint,but a soluble PD-1(sPDl)block PD-L1 as well.So far we understand that applying sPDl to interference with PD1/PD-L1 during antigen presentation restores T cell activation,which means a lot for clinical trials.Previously we study the MUC1 VNTR and survivin associated gene vaccine(MS vaccine).To enhance vaccine-induced T cell responses,we optimize DNA vaccine with sPD1 and MS antigen fusing together.We intend to investigate whether sPD1/MS vaccine enhance MS-specific T cell activation or not.To compare with MS vaccine,sPD1/MS induces a stronger humoral and cellular immunity in mice.Technically,the sPDl-based vaccine targeting MUC1/Survivin should work well with sPDl and MS co-injection.In order to maximize the immunity effect of sPD1-based vaccine,we study the sPDl/MS fusion form and co-injection form in mice to tell the difference.As a result,vaccine express sPD1 protein alone do not induce specific T cell responses.On the other hand,both of the sPD1-based vaccines have postive responses,but the sPDl/MS fusion one obviously tend to be more effective.Besides,compared with MS vaccine,sPDl/MS leads to higher levels of Thl and Th2.To explore the mechanism of sPD1,we test a series cytokines mRNA expression.It turns out that the sPDl/MS mice,expresses two fold relative CD86 mRNA(a marker represents maturation of dendric cells)than PBS in lymph node.Futhermore,we explore the ability of DC uptaking Survivin-antigen in sPDl/MS group has been amplified,as well as other upregulation of cytokines including CD80?CD86?IL-6?IL-12.PD-L1 and GzmB.There is only part of cytokines like IL12 p35 and IL12 p40 mRNA upregulated in sPD1-vaccine group.In that case,we hypothesis that the soluble PD-1 proitein enhance T cell activation in an adjuvant way.Next,we measure the tumor growth and survival percent in tumor burdon mice of melanoma and colorectal cancer.Compared with the MS vaccination mice,the sPDl/MS group has significantly inhibit tumor growth and prolong survival days.Synergize sPDl/MS vaccine with oxaliplatin,the tumor volume has been narrowed in small size.In conclusion,the sPDl-based DNA vaccine targeting MUC1 and survivin increases tumor-specific T cell activations by upregulating DC maturation cytokines.More over,sPDl/MS vaccine is responsible for the antitumor effects in tumor burdon mice.And all of these results provide us valuable experience of sPDl-based MS vaccine applying in the clinical trials some day in future.