Abstract
AbstarctBackgroundCytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy. However, unmodified CpG are not very efficient in clinical trials. Glucose, ligand of C-type lectin receptors (CLRs), can promote DC maturation and antigen presentation, which is the first step of induction of adaptive immune responses. Therefore, conjugation of type B CpG DNA to glucose-containing glycopolymers may enhance the therapeutic effects against tumor by CpG-based vaccine.MethodsgCpG was developed by chemical conjugation of type B CpG DNA to glucose-containing glycopolymers. The therapeutic effects of gCpG-based vaccine were tested in both murine primary melanoma model and its metastasis model.ResultsgCpG based tumor vaccine inhibited both primary and metastasis of melanoma in mice which was dependent on CD8 + T cells and IFNγ. In tumor microenvironment, gCpG treatment increased Th1 and CTL infiltration, increased M1 macrophages, decreased Tregs and MDSCs populations, and promoted inflammatory milieu with enhanced secretion of IFNγ and TNFα. The anti-tumor efficacy of gCpG was dramatically enhanced when combined with anti-PD1 immunotherapy.ConclusionsWe confirmed that gCpG was a promising adjuvant for vaccine formulation by activating both tumor-specific Th1 and Tc1 responses, and regulating tumor microenvironments.Graphical
Highlights
Cytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy
The main reasons of the failure of unmodified CpG-based tumor vaccines are those: (1) unmodified CpG stimulates relatively weak CytotoxicT lymphocyte (CTL) response in vivo, and (2) in tumor microenvironment (TME), CTL is always inhibited by immune suppressive cells, including tumor-associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [11,12,13]
Results gCpG inhibits tumor growth and promotes T cell responses in primary melanoma gCpG can enhance the expression of secreted embryonic alkaline phosphatase (SEAP) by macrophages [18], indicating that glycopolymer-modification can improve the CpG’s immune stimulatory activity
Summary
Cytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy. Ligand of C-type lectin receptors (CLRs), can promote DC maturation and antigen presentation, which is the first step of induction of adaptive immune responses. Conjugation of type B CpG DNA to glucose-containing glycopolymers may enhance the therapeutic effects against tumor by CpG-based vaccine. Toll-like receptor (TLR) agonists have been widely tested as vaccine adjuvants, since they can stimulate innate immune response, followed by adaptive immune response [4]. Unmethylated CpG, agonist of TLR9, activates type I immunity and has been widely used as adjuvant to stimulate CTLs. unmodified CpG-based tumor vaccines are not very efficient in clinical trials [10]. CLRs signal is important for antigen presentation on DCs maturation, which further induce adaptive immunity. Lack of glucose dampens antitumor activities of tumor-infiltrating
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