DNA vaccines targeting the encoded antigens to dendritic cells induce potent antitumor immunity in mice
1Interventional Oncology, Dahua Hospital, Xuhui District, Shanghai 200237, China.
Background:
Although DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models.
Results:
In vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice.
Conclusion:
Our findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen-specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment.
Insights
Targeting dendritic cells (DC) with DNA vaccines enhances anti-tumor immunity. Combining DC-targeted DNA vaccines with regulatory T cell (Treg) depletion effectively treats established breast cancer in mice.
Area of Science:
- Immunology
- Oncology
- Vaccine Development
Background:
- DNA vaccines show promise for cancer immunotherapy but often fail to induce durable anti-tumor immunity.
- Dendritic cells (DCs) are crucial for antigen processing and presentation in initiating immune responses.
- Targeting DCs can potentially enhance the efficacy of cancer vaccines.
Purpose of the Study:
- To develop and evaluate a DC-targeted DNA vaccine for HER2/neu-positive breast cancer.
- To investigate the anti-tumor efficacy and underlying mechanisms of this targeted vaccine in mouse models.
- To assess the combination therapy of DC-targeted DNA vaccine with regulatory T cell (Treg) depletion.
Main Methods:
- Constructed a DC-targeting DNA vaccine by fusing HER2/neu antigen to a single-chain antibody fragment (scFvNLDC-145) targeting DEC-205 on DCs.
- Administered the vaccine in mouse breast cancer models (D2F2/E2 and BALB-neuT).
- Evaluated immune responses (cellular and humoral), tumor protection, and tumor regression, with and without Treg depletion using cyclophosphamide.
Main Results:
- The scFvNLDC-145 targeted DNA vaccine successfully delivered antigens to DCs in vivo.
- Vaccination significantly enhanced HER2/neu-specific cellular and humoral immune responses, inducing long-lasting immune memory.
- The targeted vaccine provided protection against HER2/neu-positive tumors and, when combined with Treg depletion, induced regression of established tumors and retarded spontaneous tumor development.
Conclusions:
- DC-targeted DNA vaccines can induce potent antigen-specific immune responses.
- Combining DC-targeted DNA vaccines with Treg depletion offers significant therapeutic anti-tumor activity.
- This approach provides a strong rationale for developing targeted DNA vaccines for cancer treatment.
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