Enhancement of dendritic cell-based vaccine potency by targeting antigen to endosomal/lysosomal compartments
Tae Heung Kang1, Jin Hyup Lee, Hyun Cheol Bae
1Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, 516 Gojan-1 Dong, Ansan-Si, Gyeonggi-Do 425-707, South Korea.
Abstract:
Dendritic cells (DCs) are the central players in cancer immunotherapy because of their distinct ability to prime immune responses. In previous work with DNA vaccines, we described an intracellular targeting approach that routed a nuclear/cytoplasmic antigen, human papillomavirus (HPV) type 16 E7, into the endosomal and lysosomal compartments. It does so by linking E7 with the sorting signal of lysosome-associated membrane protein 1 (Sig/LAMP-1) to enhance the presentation of E7 antigen to MHC class I-restricted CD8(+) T cells, as well as to MHC class II-restricted CD4(+) T cells. To date, the Sig/LAMP-1 targeting strategy has not been tested in the context of DC-based vaccines. This study was designed to determine whether targeting HPV-16 E7 to the endosomal/lysosomal compartment can enhance the potency of DC vaccines. In immunological studies, DC-Sig/E7/LAMP-1 dramatically increased in vitro activation and in vivo expansion of E7-specific CD4(+) and CD8(+) T cells, compared with DC-E7 and DC-No insert. More importantly, in both tumor prevention and tumor treatment assays, DC-Sig/E7/LAMP-1 generated greater anti-tumor immunity against TC-1 than DC-E7. Our results demonstrate that linkage of the antigen gene to an endosomal/lysosomal targeting signal may greatly enhance the potency of DC-based vaccines.
Insights
Targeting human papillomavirus (HPV) E7 antigen to the endosomal/lysosomal compartment using Sig/LAMP-1 enhanced dendritic cell (DC) vaccine potency. This strategy significantly boosted anti-tumor immunity in preclinical models.
Area of Science:
- Immunology
- Vaccinology
- Oncology
Background:
- Dendritic cells (DCs) are crucial for initiating anti-cancer immune responses.
- Previous DNA vaccine studies showed lysosomal targeting of human papillomavirus (HPV) type 16 E7 antigen enhances T cell priming.
- The efficacy of lysosomal targeting in DC-based vaccines remained unexplored.
Purpose of the Study:
- To investigate if targeting HPV-16 E7 antigen to the endosomal/lysosomal pathway enhances the effectiveness of dendritic cell (DC) vaccines.
- To evaluate the impact of Sig/LAMP-1 mediated antigen targeting on anti-tumor immunity.
Main Methods:
- Constructed a dendritic cell vaccine (DC-Sig/E7/LAMP-1) that targets HPV-16 E7 antigen to endosomes/lysosomes via the Sig/LAMP-1 signal.
- Compared the immune response generated by DC-Sig/E7/LAMP-1 with control vaccines (DC-E7 and DC-No insert) in vitro and in vivo.
- Assessed anti-tumor immunity in tumor prevention and treatment models using TC-1 cells.
Main Results:
- DC-Sig/E7/LAMP-1 significantly enhanced the in vitro activation and in vivo expansion of E7-specific CD4(+) and CD8(+) T cells compared to controls.
- DC-Sig/E7/LAMP-1 vaccination resulted in superior anti-tumor immunity against TC-1 tumors in both prevention and treatment settings.
- The Sig/LAMP-1 targeting strategy markedly improved the potency of the DC-based vaccine.
Conclusions:
- Targeting antigens to the endosomal/lysosomal compartment via Sig/LAMP-1 is a viable strategy to enhance DC vaccine efficacy.
- This approach improves antigen presentation and subsequent T cell responses, leading to stronger anti-tumor immunity.
- Lysosomal targeting of antigens represents a promising method for developing more potent cancer vaccines.
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