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The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector.

Li R, Hu H, Ma H, Chen L, Zhou B, Liu Y, Liang C - Mol. Biol. Rep. (2013)

Bottom Line: To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene.More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs).Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect.

View Article: PubMed Central - PubMed

ABSTRACT
To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene. AAV Helper-Free system was used for rAAV-SLC package. The anti-tumor effect of SLC was detected by bearing tumor established from Hepal-6 cells both in C57BL/6J and nude mice. Flow cytometry analysis and IHC for Tumor-infiltrating T cells and CD11c+DCs were also investigated to explore the immunological mechanism. rAAV-SLC was successfully packaged in AAV293 cells and transfected Hepal-6 tumor cells at high efficiency. The anti-tumor effect was demonstrated by less tumor weight and longer survival outcome. Coincident with the anti-tumor response, local elaboration of SLC within the tumor bed elicited a heavy infiltration of CD4+, CD8+T cells and CD11c+ dendritic cells into the tumor sites. More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs). Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect. The study also suggested that Tregs in the tumor microenvironment tampered the anti-tumor effect.

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rAAV induced potent antitumor effect in vivo. a In C57BL/6J mice and b nude mice, the local expression of SLC in tumor sites was analyzed by Western-blot assay; c, d SLC-producing tumors showed a delayed progression and restrained in tumor weight when compared to rAAV-GFP tumors. No difference was observed between GFP-expressing and mock background tumors; e, f SLC-production was also associated with significantly improved survival. There was a worse survival in nude mice models, compared with C57BL/6J mice models. Bars SD, **p < 0.01 compared with rAAV-GFP group, *p < 0.05 compared with rAAV-SLC group; i.t., intra-tumor injection
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Fig2: rAAV induced potent antitumor effect in vivo. a In C57BL/6J mice and b nude mice, the local expression of SLC in tumor sites was analyzed by Western-blot assay; c, d SLC-producing tumors showed a delayed progression and restrained in tumor weight when compared to rAAV-GFP tumors. No difference was observed between GFP-expressing and mock background tumors; e, f SLC-production was also associated with significantly improved survival. There was a worse survival in nude mice models, compared with C57BL/6J mice models. Bars SD, **p < 0.01 compared with rAAV-GFP group, *p < 0.05 compared with rAAV-SLC group; i.t., intra-tumor injection

Mentions: The local expression of SLC in tumor sites of tumor bearing mice models were analyzed by Western-blot assay, we found the local expression of SLC in the tumors established from Hepal-6 cell lines previously transfected by rAAV-SLC. There was lower level local expression of SLC in the group of intra-tumor (i.t.) injection of rAAV-SLC into established tumors, as shown in Fig. 2a, b. The effect of rAAV-induced local expression SLC to enhance antitumor immune responses was subsequently tested. To elucidate in detail the mechanism of rAAV-SLC anti-tumor effect, we also examined its effect in nude mice. SLC-producing tumors showed an obviously delayed progression when compared to rAAV-GFP tumors (p < 0.01). rAAV-SLC had stronger anti-tumor effect compared with i.t.rAAV-SLC treated group (p < 0.05) in C57BL/6J mice. No difference was observed between GFP-expressing and normal background tumors, as shown in Fig. 2c, d. In parallel to reduced growth, SLC local expression was also associated with significantly improved survival as shown in Fig. 2e, f. The development of tumors was faster in nude mice than in C57BL/6J mice, and showed poorer survival.Fig. 2


The anti-tumor effect and increased tregs infiltration mediated by rAAV-SLC vector.

Li R, Hu H, Ma H, Chen L, Zhou B, Liu Y, Liang C - Mol. Biol. Rep. (2013)

rAAV induced potent antitumor effect in vivo. a In C57BL/6J mice and b nude mice, the local expression of SLC in tumor sites was analyzed by Western-blot assay; c, d SLC-producing tumors showed a delayed progression and restrained in tumor weight when compared to rAAV-GFP tumors. No difference was observed between GFP-expressing and mock background tumors; e, f SLC-production was also associated with significantly improved survival. There was a worse survival in nude mice models, compared with C57BL/6J mice models. Bars SD, **p < 0.01 compared with rAAV-GFP group, *p < 0.05 compared with rAAV-SLC group; i.t., intra-tumor injection
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824217&req=5

Fig2: rAAV induced potent antitumor effect in vivo. a In C57BL/6J mice and b nude mice, the local expression of SLC in tumor sites was analyzed by Western-blot assay; c, d SLC-producing tumors showed a delayed progression and restrained in tumor weight when compared to rAAV-GFP tumors. No difference was observed between GFP-expressing and mock background tumors; e, f SLC-production was also associated with significantly improved survival. There was a worse survival in nude mice models, compared with C57BL/6J mice models. Bars SD, **p < 0.01 compared with rAAV-GFP group, *p < 0.05 compared with rAAV-SLC group; i.t., intra-tumor injection
Mentions: The local expression of SLC in tumor sites of tumor bearing mice models were analyzed by Western-blot assay, we found the local expression of SLC in the tumors established from Hepal-6 cell lines previously transfected by rAAV-SLC. There was lower level local expression of SLC in the group of intra-tumor (i.t.) injection of rAAV-SLC into established tumors, as shown in Fig. 2a, b. The effect of rAAV-induced local expression SLC to enhance antitumor immune responses was subsequently tested. To elucidate in detail the mechanism of rAAV-SLC anti-tumor effect, we also examined its effect in nude mice. SLC-producing tumors showed an obviously delayed progression when compared to rAAV-GFP tumors (p < 0.01). rAAV-SLC had stronger anti-tumor effect compared with i.t.rAAV-SLC treated group (p < 0.05) in C57BL/6J mice. No difference was observed between GFP-expressing and normal background tumors, as shown in Fig. 2c, d. In parallel to reduced growth, SLC local expression was also associated with significantly improved survival as shown in Fig. 2e, f. The development of tumors was faster in nude mice than in C57BL/6J mice, and showed poorer survival.Fig. 2

Bottom Line: To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene.More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs).Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect.

View Article: PubMed Central - PubMed

ABSTRACT
To explore the anti-tumor effect and immune mechanism mediated by a new recombinant adeno-associated virus (rAAV) encoding secondary lymphoid tissue chemokine (SLC) mature peptide gene. AAV Helper-Free system was used for rAAV-SLC package. The anti-tumor effect of SLC was detected by bearing tumor established from Hepal-6 cells both in C57BL/6J and nude mice. Flow cytometry analysis and IHC for Tumor-infiltrating T cells and CD11c+DCs were also investigated to explore the immunological mechanism. rAAV-SLC was successfully packaged in AAV293 cells and transfected Hepal-6 tumor cells at high efficiency. The anti-tumor effect was demonstrated by less tumor weight and longer survival outcome. Coincident with the anti-tumor response, local elaboration of SLC within the tumor bed elicited a heavy infiltration of CD4+, CD8+T cells and CD11c+ dendritic cells into the tumor sites. More importantly, there was higher infiltration of Foxp3+ regulatory T cells (Tregs). Local elaboration of SLC mediated by rAAV-SLC has strong T cell mediated anti-tumor effect. The study also suggested that Tregs in the tumor microenvironment tampered the anti-tumor effect.

Show MeSH
Related in: MedlinePlus