Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response

Claudia Chiodoni, Paola Paglia, Antonella Stoppacciaro, Monica Rodolfo, Mariella Parenza, Mario P. Colombo

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Abstract

We transduced BALB/c-derived C-26 colon carcinoma cells with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (CD40L) genes to favor interaction of these cells with host dendritic cells (DCs) and, therefore, cross-priming. Cotransduced cells showed reduced tumorigenicity, and tumor take was followed by regression in some mice. In vivo tumors were heavily infiltrated with DCs that were isolated, phenotyped, and tested in vitro for stimulation of tumor-specific cytotoxic T lymphocytes (CTLs). BALB/c C-26 carcinoma cells express the endogenous murine leukemia virus (MuLV) env gene as a tumor-associated antigen. This antigen is shared among solid tumors of BALB/c and C57BL/6 mice and contains two epitopes, AH- 1 and KSP, recognized in the context of major histocompatibility complex class I molecules H-2L(d) and H-2L(b), respectively. DCs isolated from C- 26/GM/CD40L tumors grown in (BALB/c x C57BL/6)F1 mice (H-2(dxb)) stimulated interferon γ production by both anti-AH-1 and KSP CTLs, whereas tumor- infiltrating DCs (TIDCs) of BALB/c mice stimulated only anti-AH-1 CTLs. Furthermore, TIDCs primed naive mice for CTL activity as early as 2 d after injection into the footpad, whereas double-transduced tumor cells required at least 5 d for printing; this difference may reflect direct DC priming versus indirect tumor cell priming. Immunohistochemical staining indicated colocalization of DCs and apoptotic bodies in the tumors. These data indicate that DCs infiltrating tumors that produce GM-CSF and CD40L can capture cellular antigens, likely through uptake of apoptotic bodies, and mature in situ to a stage suitable for antigen presentation. Thus, tumor cell-based vaccines engineered to favor the interaction with host DCs can be considered.

Original languageEnglish
Pages (from-to)125-133
Number of pages9
JournalJournal of Experimental Medicine
Volume190
Issue number1
DOIs
Publication statusPublished - Jul 5 1999

Fingerprint

CD40 Ligand
Cytotoxic T-Lymphocytes
Neoplasm Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Dendritic Cells
Genes
Neoplasms
Cross-Priming
env Genes
Carcinoma
Antigens
Murine Leukemia Viruses
Printing
Antigen Presentation
Major Histocompatibility Complex
Inbred C57BL Mouse
Cell Communication
Interferons
Epitopes
Colon

Keywords

  • CD40 ligand
  • Cross-Priming
  • Dendritic cell
  • Granulocyte/macrophage colony-stimulating factor
  • Tumor antigens

ASJC Scopus subject areas

  • Immunology

Cite this

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title = "Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response",
abstract = "We transduced BALB/c-derived C-26 colon carcinoma cells with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (CD40L) genes to favor interaction of these cells with host dendritic cells (DCs) and, therefore, cross-priming. Cotransduced cells showed reduced tumorigenicity, and tumor take was followed by regression in some mice. In vivo tumors were heavily infiltrated with DCs that were isolated, phenotyped, and tested in vitro for stimulation of tumor-specific cytotoxic T lymphocytes (CTLs). BALB/c C-26 carcinoma cells express the endogenous murine leukemia virus (MuLV) env gene as a tumor-associated antigen. This antigen is shared among solid tumors of BALB/c and C57BL/6 mice and contains two epitopes, AH- 1 and KSP, recognized in the context of major histocompatibility complex class I molecules H-2L(d) and H-2L(b), respectively. DCs isolated from C- 26/GM/CD40L tumors grown in (BALB/c x C57BL/6)F1 mice (H-2(dxb)) stimulated interferon γ production by both anti-AH-1 and KSP CTLs, whereas tumor- infiltrating DCs (TIDCs) of BALB/c mice stimulated only anti-AH-1 CTLs. Furthermore, TIDCs primed naive mice for CTL activity as early as 2 d after injection into the footpad, whereas double-transduced tumor cells required at least 5 d for printing; this difference may reflect direct DC priming versus indirect tumor cell priming. Immunohistochemical staining indicated colocalization of DCs and apoptotic bodies in the tumors. These data indicate that DCs infiltrating tumors that produce GM-CSF and CD40L can capture cellular antigens, likely through uptake of apoptotic bodies, and mature in situ to a stage suitable for antigen presentation. Thus, tumor cell-based vaccines engineered to favor the interaction with host DCs can be considered.",
keywords = "CD40 ligand, Cross-Priming, Dendritic cell, Granulocyte/macrophage colony-stimulating factor, Tumor antigens",
author = "Claudia Chiodoni and Paola Paglia and Antonella Stoppacciaro and Monica Rodolfo and Mariella Parenza and Colombo, {Mario P.}",
year = "1999",
month = "7",
day = "5",
doi = "10.1084/jem.190.1.125",
language = "English",
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T1 - Dendritic cells infiltrating tumors cotransduced with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand genes take up and present endogenous tumor-associated antigens, and prime naive mice for a cytotoxic T lymphocyte response

AU - Chiodoni, Claudia

AU - Paglia, Paola

AU - Stoppacciaro, Antonella

AU - Rodolfo, Monica

AU - Parenza, Mariella

AU - Colombo, Mario P.

PY - 1999/7/5

Y1 - 1999/7/5

N2 - We transduced BALB/c-derived C-26 colon carcinoma cells with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (CD40L) genes to favor interaction of these cells with host dendritic cells (DCs) and, therefore, cross-priming. Cotransduced cells showed reduced tumorigenicity, and tumor take was followed by regression in some mice. In vivo tumors were heavily infiltrated with DCs that were isolated, phenotyped, and tested in vitro for stimulation of tumor-specific cytotoxic T lymphocytes (CTLs). BALB/c C-26 carcinoma cells express the endogenous murine leukemia virus (MuLV) env gene as a tumor-associated antigen. This antigen is shared among solid tumors of BALB/c and C57BL/6 mice and contains two epitopes, AH- 1 and KSP, recognized in the context of major histocompatibility complex class I molecules H-2L(d) and H-2L(b), respectively. DCs isolated from C- 26/GM/CD40L tumors grown in (BALB/c x C57BL/6)F1 mice (H-2(dxb)) stimulated interferon γ production by both anti-AH-1 and KSP CTLs, whereas tumor- infiltrating DCs (TIDCs) of BALB/c mice stimulated only anti-AH-1 CTLs. Furthermore, TIDCs primed naive mice for CTL activity as early as 2 d after injection into the footpad, whereas double-transduced tumor cells required at least 5 d for printing; this difference may reflect direct DC priming versus indirect tumor cell priming. Immunohistochemical staining indicated colocalization of DCs and apoptotic bodies in the tumors. These data indicate that DCs infiltrating tumors that produce GM-CSF and CD40L can capture cellular antigens, likely through uptake of apoptotic bodies, and mature in situ to a stage suitable for antigen presentation. Thus, tumor cell-based vaccines engineered to favor the interaction with host DCs can be considered.

AB - We transduced BALB/c-derived C-26 colon carcinoma cells with granulocyte/macrophage colony-stimulating factor (GM-CSF) and CD40 ligand (CD40L) genes to favor interaction of these cells with host dendritic cells (DCs) and, therefore, cross-priming. Cotransduced cells showed reduced tumorigenicity, and tumor take was followed by regression in some mice. In vivo tumors were heavily infiltrated with DCs that were isolated, phenotyped, and tested in vitro for stimulation of tumor-specific cytotoxic T lymphocytes (CTLs). BALB/c C-26 carcinoma cells express the endogenous murine leukemia virus (MuLV) env gene as a tumor-associated antigen. This antigen is shared among solid tumors of BALB/c and C57BL/6 mice and contains two epitopes, AH- 1 and KSP, recognized in the context of major histocompatibility complex class I molecules H-2L(d) and H-2L(b), respectively. DCs isolated from C- 26/GM/CD40L tumors grown in (BALB/c x C57BL/6)F1 mice (H-2(dxb)) stimulated interferon γ production by both anti-AH-1 and KSP CTLs, whereas tumor- infiltrating DCs (TIDCs) of BALB/c mice stimulated only anti-AH-1 CTLs. Furthermore, TIDCs primed naive mice for CTL activity as early as 2 d after injection into the footpad, whereas double-transduced tumor cells required at least 5 d for printing; this difference may reflect direct DC priming versus indirect tumor cell priming. Immunohistochemical staining indicated colocalization of DCs and apoptotic bodies in the tumors. These data indicate that DCs infiltrating tumors that produce GM-CSF and CD40L can capture cellular antigens, likely through uptake of apoptotic bodies, and mature in situ to a stage suitable for antigen presentation. Thus, tumor cell-based vaccines engineered to favor the interaction with host DCs can be considered.

KW - CD40 ligand

KW - Cross-Priming

KW - Dendritic cell

KW - Granulocyte/macrophage colony-stimulating factor

KW - Tumor antigens

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DO - 10.1084/jem.190.1.125

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