Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

• Published in: Biomaterials 2015-01, Vol.38, p.50-60
• Main Authors: Luo, Zichao, Wang, Ce, Yi, Huqiang, Li, Ping, Pan, Hong, Liu, Lanlan, Cai, Lintao, Ma, Yifan
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Biocompatibility; Biomedical materials; Cancer; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; Cell Line, Tumor; Cell Survival - drug effects; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - pathology; Dentistry; Humans; In vivo testing; In vivo tests; Melanoma - immunology; Melanoma - pathology; Melanoma - therapy; Mice; Mice, Inbred C57BL; Nanocapsules - administration & dosage; Nanocapsules - chemistry; Nanocapsules - ultrastructure; Nanostructure; Nanovaccine; Poly I-C - administration & dosage; Poly I-C - immunology; Polypeptide micelles; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; STAT3 siRNA; Surgical implants; TLR3 agonist; Transfection - methods; Treatment Outcome; Tumor immunosuppression; Tumor-associated dendritic cells; Tumors
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2014.10.050

Abstract Although cancer vaccine-based immunotherapy holds great potential for cancer treatment, tumor-induced dendritic cell (DC) dysfunction remains to be the major obstacle for developing effective vaccines. Compared with normal DCs, tumor-associated DCs (TADCs) are less matured with poor responsiveness to Toll-like receptor (TLR) stimulation, which has been related with STAT3 hyperactivity. In the present study, Poly I:C (PIC, a TLR3 agonist), STAT3 siRNA and OVA antigen were co-encapsulated by poly (ethylene glycol)-b-poly ( l -lysine)-b-poly ( l -leucine) (PEG-PLL-PLLeu) polypeptide micelles to generate PMP/OVA/siRNA nanovaccine, which was aimed to effectively overcome DC dysfunction in vivo by deleting STAT3 gene in situ. The results showed that PMP/OVA/siRNA simultaneously facilitated the cellular uptake of OVA antigen and siRNA about 3–200 folds, and decreased STAT3 expression in TADCs over 50% both in vitro and in vivo . PMP/OVA/siRNA also elevated CD86 and CD40 expression as well as IL-12 production by TADCs more effectively than PMP/OVA did, indicating its strong potency of inducing TADC maturation and activation. Moreover, the immunization of PMP/OVA/siRNA rather than PMP/OVA effectively abrogated immunosuppression in the tumor microenvironment by increasing mature DCs and decreasing immunosuppressive cells in tumor-draining lymph nodes, which thereby led to potent anti-tumor immune responses and dramatic tumor regression with prolonged survival. Hence, in vivo co-delivery of immunopotentiator (PIC) and immunosuppressive gene silencer (STAT3 siRNA) by nanovaccines are expected to be a promising strategy to improve the therapeutic efficacy of cancer vaccines by modulating TADCs and overcoming tumor immunosupression.