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Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

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Suppression of preestablished lung metastases by administration of modified XS52 DCs. Shown  are examples and quantitative data of treatment effect on preestablished lung metastases induced by XS52-Adβgal immunization. 3 d after the establishment of diffuse lung metastases in BALB/c mice with intravenous  administration of 3 × 104 CT26.CL25 cells, 3 × 105 XS52-AdNull or XS52-Adβgal were administered subcutaneously to the tumor-bearing mice. 20 d after tumor implantation, the mice were killed, and their lungs  were harvested, fixed, and stained for βgal expression with X-Gal. (A) Example of lungs from a nonimmunized  mouse. (B) Example of lungs from a mouse receiving XS52-AdNull treatment. (C and D) Examples of lungs  from mice receiving XS52-Adβgal treatment. (E) Quantification of the number of lung metastases in untreated, XS52-AdNull– and XS52-Adβgal–treated mice with preestablished lung metastases. Using a dissecting  microscope, surface blue-staining (βgal+) lung metastases were enumerated. Each data point represents an individual animal. Only metastatic deposits ⩽250 could be reliably enumerated; lungs with >250 metastases  were assigned an empirical number of 250.
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Figure 5: Suppression of preestablished lung metastases by administration of modified XS52 DCs. Shown are examples and quantitative data of treatment effect on preestablished lung metastases induced by XS52-Adβgal immunization. 3 d after the establishment of diffuse lung metastases in BALB/c mice with intravenous administration of 3 × 104 CT26.CL25 cells, 3 × 105 XS52-AdNull or XS52-Adβgal were administered subcutaneously to the tumor-bearing mice. 20 d after tumor implantation, the mice were killed, and their lungs were harvested, fixed, and stained for βgal expression with X-Gal. (A) Example of lungs from a nonimmunized mouse. (B) Example of lungs from a mouse receiving XS52-AdNull treatment. (C and D) Examples of lungs from mice receiving XS52-Adβgal treatment. (E) Quantification of the number of lung metastases in untreated, XS52-AdNull– and XS52-Adβgal–treated mice with preestablished lung metastases. Using a dissecting microscope, surface blue-staining (βgal+) lung metastases were enumerated. Each data point represents an individual animal. Only metastatic deposits ⩽250 could be reliably enumerated; lungs with >250 metastases were assigned an empirical number of 250.

Mentions: To evaluate if tumor protection after DC immunization could be extended to a more stringent and clinically relevant model, Adβgal-modified XS52 were used to treat mice with preexisting tumors. In this experiment, diffuse lung metastases were first generated in BALB/c mice by intravenous administration of 3 × 104 CT26.CL25 tumor cells. 3 d after tumor implantation, the mice were either left untreated or were treated with subcutaneous administration of 3 × 105 XS52–AdNull modified cells or XS52-Adβgal–modified cells. Tumor-bearing mice that were not immunized (Fig. 5, A) or those that were immunized with the control DCs (XS52-AdNull; B) exhibited multiple lung metastases 20 d after tumor implantation. In contrast, tumor-bearing mice which received XS52-Adβgal treatment demonstrated a striking reduction in the number of metastases (C and D), demonstrating that DCs genetically modified to express a tumor antigen could effectively suppress preexisting tumors. Quantitative analysis of the number of metastatic nodules confirmed the significant treatment differences between XS52-Adβgal–treated group and the control groups (P <0.009; E). In contrast, XS52-Adβgal cells that had been lysed by repeated freezing and thawing did not confer any therapeutic effect when compared to untreated or XS52-AdNull–treated animals (P >0.4; not shown).


Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Suppression of preestablished lung metastases by administration of modified XS52 DCs. Shown  are examples and quantitative data of treatment effect on preestablished lung metastases induced by XS52-Adβgal immunization. 3 d after the establishment of diffuse lung metastases in BALB/c mice with intravenous  administration of 3 × 104 CT26.CL25 cells, 3 × 105 XS52-AdNull or XS52-Adβgal were administered subcutaneously to the tumor-bearing mice. 20 d after tumor implantation, the mice were killed, and their lungs  were harvested, fixed, and stained for βgal expression with X-Gal. (A) Example of lungs from a nonimmunized  mouse. (B) Example of lungs from a mouse receiving XS52-AdNull treatment. (C and D) Examples of lungs  from mice receiving XS52-Adβgal treatment. (E) Quantification of the number of lung metastases in untreated, XS52-AdNull– and XS52-Adβgal–treated mice with preestablished lung metastases. Using a dissecting  microscope, surface blue-staining (βgal+) lung metastases were enumerated. Each data point represents an individual animal. Only metastatic deposits ⩽250 could be reliably enumerated; lungs with >250 metastases  were assigned an empirical number of 250.
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Related In: Results  -  Collection

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Figure 5: Suppression of preestablished lung metastases by administration of modified XS52 DCs. Shown are examples and quantitative data of treatment effect on preestablished lung metastases induced by XS52-Adβgal immunization. 3 d after the establishment of diffuse lung metastases in BALB/c mice with intravenous administration of 3 × 104 CT26.CL25 cells, 3 × 105 XS52-AdNull or XS52-Adβgal were administered subcutaneously to the tumor-bearing mice. 20 d after tumor implantation, the mice were killed, and their lungs were harvested, fixed, and stained for βgal expression with X-Gal. (A) Example of lungs from a nonimmunized mouse. (B) Example of lungs from a mouse receiving XS52-AdNull treatment. (C and D) Examples of lungs from mice receiving XS52-Adβgal treatment. (E) Quantification of the number of lung metastases in untreated, XS52-AdNull– and XS52-Adβgal–treated mice with preestablished lung metastases. Using a dissecting microscope, surface blue-staining (βgal+) lung metastases were enumerated. Each data point represents an individual animal. Only metastatic deposits ⩽250 could be reliably enumerated; lungs with >250 metastases were assigned an empirical number of 250.
Mentions: To evaluate if tumor protection after DC immunization could be extended to a more stringent and clinically relevant model, Adβgal-modified XS52 were used to treat mice with preexisting tumors. In this experiment, diffuse lung metastases were first generated in BALB/c mice by intravenous administration of 3 × 104 CT26.CL25 tumor cells. 3 d after tumor implantation, the mice were either left untreated or were treated with subcutaneous administration of 3 × 105 XS52–AdNull modified cells or XS52-Adβgal–modified cells. Tumor-bearing mice that were not immunized (Fig. 5, A) or those that were immunized with the control DCs (XS52-AdNull; B) exhibited multiple lung metastases 20 d after tumor implantation. In contrast, tumor-bearing mice which received XS52-Adβgal treatment demonstrated a striking reduction in the number of metastases (C and D), demonstrating that DCs genetically modified to express a tumor antigen could effectively suppress preexisting tumors. Quantitative analysis of the number of metastatic nodules confirmed the significant treatment differences between XS52-Adβgal–treated group and the control groups (P <0.009; E). In contrast, XS52-Adβgal cells that had been lysed by repeated freezing and thawing did not confer any therapeutic effect when compared to untreated or XS52-AdNull–treated animals (P >0.4; not shown).

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Show MeSH
Related in: MedlinePlus