Abstract
Dendritic cells (DCs) are antigen-presenting cells involved in T cell activation and differentiation to regulate immune responses. Lipoimmunogens can be developed as pharmaceutical lipoproteins for cancer immunotherapy to target DCs via toll-like receptor 2 (TLR2) signaling. Previously, we constructed a lipoimmunogen, a lipidated human papillomavirus (HPV) E7 inactive mutant (rlipoE7m), to inhibit the growth of HPV16 E7-expressing tumor cells in a murine model. Moreover, this antitumor effect could be enhanced by a combinatory treatment with CpG oligodeoxynucleotides (ODN). To improve safety, we developed a rlipoE7m plus DOTAP liposome-encapsulated native phosphodiester CpG (POCpG/DOTAP) treatment to target DCs to enhance antitumor immunity. We optimized the formulation of rlipoE7m and POCpG/DOTAP liposomes to promote conventional DC and plasmacytoid DC maturation in vitro and in vivo. Combination of rlipoE7m plus POCpG/DOTAP could activate conventional DCs and plasmacytoid DCs to augment IL-12 production to promote antitumor responses by intravenous injection. In addition, the combination of rlipoE7m plus POCpG/DOTAP could elicit robust cytotoxic T lymphocytes (CTLs) by intravenous immunization. Interestingly, the combination of rlipoE7m plus POCpG/DOTAP could efficiently inhibit tumor growth via intravenous immunization. Moreover, rlipoE7m plus POCpG/DOTAP combined reduced the number of tumor-infiltrating regulatory T cells dramatically due to downregulation of IL-10 production by DCs. These results showed that the combination of rlipoE7m plus POCpG/DOTAP could target DCs via intravenous delivery to enhance antitumor immunity and reduce the number of immunosuppressive cells in the tumor microenvironment.
Highlights
Overcoming immunosuppression by the tumor microenvironment is a difficult task for cancer immunotherapy [1]
A total of 2 × 106 bone marrow-derived dendritic cells (BMDCs) were treated with the indicated concentrations of rlipoE7m and phosphodiester CpG ODN (POCpG) with Dioleoyloxy-3-trimethylammonium propane (DOTAP) liposomes for 18 h, and cytokine concentrations in the supernatant were determined by ELISA
The results indicate that the recombinant lipoprotein was the major factor triggering IL-1β production
Summary
Overcoming immunosuppression by the tumor microenvironment is a difficult task for cancer immunotherapy [1]. Dendritic cells (DCs) are important for the regulation of immunological stimulation and tolerance [5,6]. DC maturation is promoted by pathogen-associated molecular pattern (PAMP) stimulation of pathogen recognition receptors. The adjuvanticity of PAMP-derived immunostimulators can promote tumor-associated antigen-induced antitumor immunity [10]. Multiple TLR agonist combinations can induce robust antitumor immunity and overcome the immunosuppression by regulatory T cells (Tregs) [11]. A TLR2 agonist recombinant lipoprotein combined with the TLR9 agonist CpG oligonucleotide (CpG ODN) could dramatically enhance antitumor efficacy and reduce the number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) [12]. A recombinant lipoprotein could increase the uptake of
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