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Dendritic cell-specific delivery of Flt3L by coronavirus vectors secures induction of therapeutic antitumor immunity.

Perez-Shibayama C, Gil-Cruz C, Nussbacher M, Allgäuer E, Cervantes-Barragan L, Züst R, Ludewig B - PLoS ONE (2013)

Bottom Line: Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs).Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15.Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

ABSTRACT
Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8(+) T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8(+) T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.

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Prophylactic and therapeutic tumor immunity against a peripheral solid tumor.(A) B6 mice were i.v. immunized with 105 pfu of the different vectors or received PBS as control. Seven days later, 5×105 gp-recombinant Lewis lung carcinoma cells were injected s.c. on the left flank. (B) Assessment of therapeutic tumor immunity induced by 105 pfu of the different vectors applied on day 4 post s.c. inoculation with 5×105 gp-recombinant Lewis lung carcinoma cells. Tumor growth was monitored on the indicated days. Values indicate mean tumor volume ±SEM (n=9 mice). Values in parentheses indicate number of growing tumors of inoculated tumors. Statistical analysis in (B) was performed using one way ANOVA with Bonferroni multiple comparison test (**, p< 0.01; ***, p< 0.001; ns, non-significant).
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pone-0081442-g005: Prophylactic and therapeutic tumor immunity against a peripheral solid tumor.(A) B6 mice were i.v. immunized with 105 pfu of the different vectors or received PBS as control. Seven days later, 5×105 gp-recombinant Lewis lung carcinoma cells were injected s.c. on the left flank. (B) Assessment of therapeutic tumor immunity induced by 105 pfu of the different vectors applied on day 4 post s.c. inoculation with 5×105 gp-recombinant Lewis lung carcinoma cells. Tumor growth was monitored on the indicated days. Values indicate mean tumor volume ±SEM (n=9 mice). Values in parentheses indicate number of growing tumors of inoculated tumors. Statistical analysis in (B) was performed using one way ANOVA with Bonferroni multiple comparison test (**, p< 0.01; ***, p< 0.001; ns, non-significant).

Mentions: Clearance of rapidly growing metastatic tumors is certainly a challenge for the immune system. However, metastatic tumors such as the B16 melanoma cells can reach secondary lymphoid organs and thereby contribute – most likely due to their MHC class I expression – to the amplification of antitumor CD8+ T cells [40]. In contrast, tumors which arise in peripheral tissues can escape immune surveillance in the absence of appropriately activated T cells [41]. To assess whether coronavirus vector-based vaccination can prevent growth of such peripherally growing tumors, we applied 5×105 LCMV-GP recombinant Lewis lung carcinoma (LLC) cells s.c. into prophylactically vaccinated B6 mice. As shown in Figure 5A, all coronavirus-based vectors were able to protect the animals under these conditions. However, when we assessed the efficacy of the vaccines in a therapeutic approach, i.e. applying the vaccines on day 4 post tumor inoculation, only FLt3L-encoding vectors achieved an almost complete block of tumor growth (Figure 5B). Taken together, these results indicate that different cytokines can improve immunogenicity of coronavirus vectors. However, maturation of DCs through vector-encoded cytokines that preferentially activate myeloid cells is essential for the generation of therapeutic tumor immunity.


Dendritic cell-specific delivery of Flt3L by coronavirus vectors secures induction of therapeutic antitumor immunity.

Perez-Shibayama C, Gil-Cruz C, Nussbacher M, Allgäuer E, Cervantes-Barragan L, Züst R, Ludewig B - PLoS ONE (2013)

Prophylactic and therapeutic tumor immunity against a peripheral solid tumor.(A) B6 mice were i.v. immunized with 105 pfu of the different vectors or received PBS as control. Seven days later, 5×105 gp-recombinant Lewis lung carcinoma cells were injected s.c. on the left flank. (B) Assessment of therapeutic tumor immunity induced by 105 pfu of the different vectors applied on day 4 post s.c. inoculation with 5×105 gp-recombinant Lewis lung carcinoma cells. Tumor growth was monitored on the indicated days. Values indicate mean tumor volume ±SEM (n=9 mice). Values in parentheses indicate number of growing tumors of inoculated tumors. Statistical analysis in (B) was performed using one way ANOVA with Bonferroni multiple comparison test (**, p< 0.01; ***, p< 0.001; ns, non-significant).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3842931&req=5

pone-0081442-g005: Prophylactic and therapeutic tumor immunity against a peripheral solid tumor.(A) B6 mice were i.v. immunized with 105 pfu of the different vectors or received PBS as control. Seven days later, 5×105 gp-recombinant Lewis lung carcinoma cells were injected s.c. on the left flank. (B) Assessment of therapeutic tumor immunity induced by 105 pfu of the different vectors applied on day 4 post s.c. inoculation with 5×105 gp-recombinant Lewis lung carcinoma cells. Tumor growth was monitored on the indicated days. Values indicate mean tumor volume ±SEM (n=9 mice). Values in parentheses indicate number of growing tumors of inoculated tumors. Statistical analysis in (B) was performed using one way ANOVA with Bonferroni multiple comparison test (**, p< 0.01; ***, p< 0.001; ns, non-significant).
Mentions: Clearance of rapidly growing metastatic tumors is certainly a challenge for the immune system. However, metastatic tumors such as the B16 melanoma cells can reach secondary lymphoid organs and thereby contribute – most likely due to their MHC class I expression – to the amplification of antitumor CD8+ T cells [40]. In contrast, tumors which arise in peripheral tissues can escape immune surveillance in the absence of appropriately activated T cells [41]. To assess whether coronavirus vector-based vaccination can prevent growth of such peripherally growing tumors, we applied 5×105 LCMV-GP recombinant Lewis lung carcinoma (LLC) cells s.c. into prophylactically vaccinated B6 mice. As shown in Figure 5A, all coronavirus-based vectors were able to protect the animals under these conditions. However, when we assessed the efficacy of the vaccines in a therapeutic approach, i.e. applying the vaccines on day 4 post tumor inoculation, only FLt3L-encoding vectors achieved an almost complete block of tumor growth (Figure 5B). Taken together, these results indicate that different cytokines can improve immunogenicity of coronavirus vectors. However, maturation of DCs through vector-encoded cytokines that preferentially activate myeloid cells is essential for the generation of therapeutic tumor immunity.

Bottom Line: Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs).Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15.Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.

ABSTRACT
Efficacy of antitumor vaccination depends to a large extent on antigen targeting to dendritic cells (DCs). Here, we assessed antitumor immunity induced by attenuated coronavirus vectors which exclusively target DCs in vivo and express either lymphocyte- or DC-activating cytokines in combination with a GFP-tagged model antigen. Tracking of in vivo transduced DCs revealed that vectors encoding for Fms-like tyrosine kinase 3 ligand (Flt3L) exhibited a higher capacity to induce DC maturation compared to vectors delivering IL-2 or IL-15. Moreover, Flt3L vectors more efficiently induced tumor-specific CD8(+) T cells, expanded the epitope repertoire, and provided both prophylactic and therapeutic tumor immunity. In contrast, IL-2- or IL-15-encoding vectors showed a substantially lower efficacy in CD8(+) T cell priming and failed to protect the host once tumors had been established. Thus, specific in vivo targeting of DCs with coronavirus vectors in conjunction with appropriate conditioning of the microenvironment through Flt3L represents an efficient strategy for the generation of therapeutic antitumor immunity.

Show MeSH
Related in: MedlinePlus