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CCL4 as an adjuvant for DNA vaccination in a Her2/neu mouse tumor model
T Nguyen-Hoai1,2,3, M Pham-Duc1,2,3, M Gries1,2,3
1Department of Hematology, Oncology, and Tumor Immunology, Charit-University Medicine Berlin, Campus Virchow, Berlin, Germany.
Abstract:
Chemokines are key regulators of both innate and adaptive immune responses. CCL4 (macrophage inflammatory protein-1β, MIP-1β) is a CC chemokine that has a broad spectrum of target cells including immature dendritic cells, which express the cognate receptor CCR5. We asked whether a plasmid encoding CCL4 is able to improve tumor protection and immune responses in a Her2/neu+ mouse tumor model. Balb/c mice were immunized twice intramuscularly with plasmid DNA on days 1 and 15. On day 25, a tumor challenge was performed with 2 × 10(5) syngeneic Her2/neu+ D2F2/E2 tumor cells. Different groups of mice were vaccinated with pDNA(Her2/neu) plus pDNA(CCL4), pDNA(Her2/neu), pDNA(CCL4) or mock vector alone. Our results show that CCL4 is able to (i) improve tumor protection and (ii) augment a TH1-polarized immune response against Her2/neu. Although Her2/neu-specific humoral and T-cell immune responses were comparable with that induced in previous studies using CCL19 or CCL21 as adjuvants, tumor protection conferred by CCL4 was inferior. Whether this is due to a different spectrum of (innate) immune cells, remains to be clarified. However, combination of CCL19/21 with CCL4 might be a reasonable approach in the future, particularly for DNA vaccination in Her2/neu+ breast cancer in the situation of minimal residual disease.
Insights
CCL4 (macrophage inflammatory protein-1β) enhances anti-tumor immunity and TH1 responses in a Her2/neu+ mouse model. While it improved tumor protection, it was less effective than other chemokines, suggesting combination therapy potential.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- Chemokines regulate immune responses; CCL4 (macrophage inflammatory protein-1β) targets cells like dendritic cells via CCR5.
- Investigating CCL4 as an adjuvant in DNA vaccination for cancer immunotherapy.
Purpose of the Study:
- To evaluate the efficacy of plasmid-encoded CCL4 in improving tumor protection and immune responses against Her2/neu+ tumors.
- To assess the impact of CCL4 on TH1-polarized immune responses in a murine tumor model.
Main Methods:
- Balb/c mice were immunized with plasmid DNA encoding Her2/neu and/or CCL4.
- Tumor challenge was performed using syngeneic Her2/neu+ D2F2/E2 tumor cells.
- Humoral and T-cell immune responses were analyzed, alongside tumor protection.
Main Results:
- CCL4 significantly improved tumor protection and augmented TH1-polarized immune responses against Her2/neu.
- Her2/neu-specific immune responses were comparable to those induced by CCL19 or CCL21 adjuvants.
- However, CCL4 conferred inferior tumor protection compared to CCL19/CCL21.
Conclusions:
- CCL4 demonstrates potential as an adjuvant in DNA vaccination for Her2/neu+ cancers.
- The inferior tumor protection by CCL4 warrants further investigation into its targeted immune cell spectrum.
- Combining CCL19/21 with CCL4 may be a promising strategy for DNA vaccination, especially in minimal residual disease settings.
