Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells

Britnie R. James; Erik L. Brincks; Tamara A. Kucaba; Louis Boon; Thomas S. Griffith

doi:10.1007/s00262-014-1548-5

Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells

Britnie R. James, Erik L. Brincks, Tamara A. Kucaba, Louis Boon, Thomas S. Griffith

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18 Scopus citations

Abstract

It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3 ^-/- BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 ^-/- BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 ^-/- BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.

Original language	English (US)
Pages (from-to)	685-697
Number of pages	13
Journal	Cancer Immunology, Immunotherapy
Volume	63
Issue number	7
DOIs	https://doi.org/10.1007/s00262-014-1548-5
State	Published - Jul 2014

Bibliographical note

Funding Information:
Acknowledgments We thank Kristin anderson (Masopust lab, Center for Immunology, University of Minnesota) for assistance with the intravascular staining protocol, and Drs. Chris Pennell and John Ohlfest (University of Minnesota) for helpful discussions. We also thank the University of Iowa gene transfer Vector Core for the production of the ad5-traIl vector. this work was supported by a University of Minnesota Doctoral Dissertation Fellowship (BrJ), a Kidney Cancer association research Scholarship administered by the american Urological association (elB), and the national Institutes of Health grants Ca109446 (tSg).

Keywords

Dendritic cells
Immunotherapy
RCC
TRAIL

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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abstract = "It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3 -/- BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 -/- BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 -/- BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.",

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author = "James, {Britnie R.} and Brincks, {Erik L.} and Kucaba, {Tamara A.} and Louis Boon and Griffith, {Thomas S.}",

note = "Funding Information: Acknowledgments We thank Kristin anderson (Masopust lab, Center for Immunology, University of Minnesota) for assistance with the intravascular staining protocol, and Drs. Chris Pennell and John Ohlfest (University of Minnesota) for helpful discussions. We also thank the University of Iowa gene transfer Vector Core for the production of the ad5-traIl vector. this work was supported by a University of Minnesota Doctoral Dissertation Fellowship (BrJ), a Kidney Cancer association research Scholarship administered by the american Urological association (elB), and the national Institutes of Health grants Ca109446 (tSg).",

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doi = "10.1007/s00262-014-1548-5",

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AU - Kucaba, Tamara A.

AU - Boon, Louis

AU - Griffith, Thomas S.

N1 - Funding Information: Acknowledgments We thank Kristin anderson (Masopust lab, Center for Immunology, University of Minnesota) for assistance with the intravascular staining protocol, and Drs. Chris Pennell and John Ohlfest (University of Minnesota) for helpful discussions. We also thank the University of Iowa gene transfer Vector Core for the production of the ad5-traIl vector. this work was supported by a University of Minnesota Doctoral Dissertation Fellowship (BrJ), a Kidney Cancer association research Scholarship administered by the american Urological association (elB), and the national Institutes of Health grants Ca109446 (tSg).

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N2 - It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3 -/- BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 -/- BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 -/- BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.

AB - It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3 -/- BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3 -/- BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3 -/- BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.

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Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells

Abstract

Bibliographical note

Keywords

UN SDGs

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