Targeting CpG Adjuvant to Lymph Node via Dextran Conjugate Enhances Antitumor Immunotherapy

Abstract

Nucleic acid based adjuvants recognized by Toll-like receptors (TLR) are potent immune system stimulants that can augment the antitumor immune responses in an antigen-specific manner. However, their clinical uses as vaccine adjuvants are limited primarily due to lack of accumulation in the lymph nodes, the anatomic sites where the immune responses are initiated. Here, we showed that chemical conjugation of type B CpG DNA, a TLR9 agonist to dextran polymer dramatically enhanced CpG's lymph node accumulation in mice. Dextran conjugation did not alter CpG ODN's uptake, internalization, and bioactivity in vitro. Delivery of Dextran-CpG conjugate markedly increased the uptake by antigen presenting cells in the lymph nodes and enhanced CD8 T cell responses primed by protein vaccines, leading to improved therapeutic antitumor immunity. Furthermore, immunization with Dextran-CpG mixed with necrotic whole tumor cells induced a protective antitumor response in a murine model, suggesting that this approach was not limited to molecularly defined antigens. This simple method might also be applicable for the delivery of many other nucleic acid based adjuvants in cancer vaccines.

An effective dendritic cell‐based vaccine containing glioma stem‐like cell lysate and CpG adjuvant for an orthotopic mouse model of glioma

“…CpG ODNs directly activate B cell proliferation, induce cytokine secretion, promote DC maturation, and facilitate antigen presentation, thereby enhancing vaccine‐specific humoral and cellular responses . As monotherapy or as an adjuvant, the use of CpG ODNs for anti‐tumor immune activity has been largely successful . Regarding immunotherapy for glioma, CpG ODN‐based treatment has reportedly induced T cell‐mediated anti‐tumor activity against murine glioma .…”

“…13,14 As monotherapy or as an adjuvant, the use of CpG ODNs for anti-tumor immune activity has been largely successful. 15,16 Regarding immunotherapy for glioma, CpG ODN-based treatment has reportedly induced T cellmediated anti-tumor activity against murine glioma. [17][18][19] Hence, we believe that CpG ODNs may serve as suitable adjuvants when designing therapeutic glioma vaccines.…”

Efficient Delivery of Tyrosinase Related Protein‐2 (TRP2) Peptides to Lymph Nodes using Serum‐Derived Exosomes

“…To ensure successful localization of biomaterials to lymph nodes, the physicochemical properties of the particles, such as the hydrodynamic size and surface charge, should be considered . For example, particles of size 10–100 nm are able to penetrate lymphatic capillaries and accumulate in the lymph nodes, whereas particles below 6 nm tend to drain into the blood vessels . Recently, exosomes (EXOs), naturally‐derived biomaterials with superior stability and biocompatibility, have received much attention for use in the lymphatic targeting of biomolecules.…”

“…In addition, EXOs were subcutaneously injected into mice in order to monitor the distribution and accumulation of EXOs in lymph nodes. Considering the superior localization of particles (10–100 nm) into lymph nodes, it was hypothesized that EXOs could be used to deliver antigen peptides into lymph nodes, where they would stimulate DCs and macrophages …”

Mannose‐Modified Serum Exosomes for the Elevated Uptake to Murine Dendritic Cells and Lymphatic Accumulation

“…Approximately 1.8‐fold greater fluorescence intensities were observed in EXO‐PEG‐man/DiI than those with EXO‐PEG‐bio/DiI. The lymphatic accumulation of immune stimulators and antigens might be important for successful immunotherapy . Thus, EXO‐PEG‐man could be used as a promising carrier for immune stimulators and tumor antigens, for example, TRP‐2 peptides to lymph nodes for immunotherapy.…”