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

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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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Abbreviations

Ad5-TRAIL:

Recombinant adenovirus encoding TRAIL

Ag:

Antigen

APC:

Antigen presenting cell

Batf3:

Basic leucine zipper transcription factor, ATF-like 3

BV650:

Brilliant Violet 650

CpG:

CpG-containing oligodeoxynucleotide

CXCL10:

C-X-C motif chemokine 10

DC:

Dendritic cell

GFP:

Green fluorescent protein

HBSS:

Hank’s buffered salt solution

IFIT:

Interferon induced proteins with tetratricopeptide repeats

IFN:

Interferon

IFNAR:

Interferon αβ receptor

IL:

Interleukin

IR:

Intrarenal

i.v.:

Intravascular

mAb:

Monoclonal antibody

IRF7:

Interferon regulatory factor 7

ISG15:

Interferon-stimulated gene 15

MDA5:

Melanoma differentiation-associated protein 5

MHC:

Major histocompatibility complex

PBS:

Phosphate-buffered saline

Mx1 (IFI78):

Interferon inducible protein 78

pDC:

Plasmacytoid dendritic cell

PDCA:

Plasmacytoid dendritic cell antigen

PE:

Phycoerytherin

RCC:

Renal cell carcinoma

Rx:

Combination Ad5-TRAIL/CpG therapy

TNF:

Tumor necrosis factor

TRAIL:

TNF-related apoptosis-inducing ligand

WT:

Wild-type

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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).

Conflict of interest

B. James, E. Brincks, T. Kucaba, and T. Griffith declare that they have no conflict of interest. L. Boon is Chief Scientific Officer at Bioceros Holding BV.

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Authors and Affiliations

  1. Department of Urology, University of Minnesota, 3-125 CCRB, 2231 6th St. SE, Minneapolis, MN, 55455, USA

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

  2. Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, MN, 55455, USA

    Britnie R. James & Thomas S. Griffith

  3. Center for Immunology, University of Minnesota, Minneapolis, MN, 55455, USA

    Thomas S. Griffith

  4. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, 55455, USA

    Thomas S. Griffith

  5. Bioceros Holding BV, Utrecht, The Netherlands

    Louis Boon

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  1. Britnie R. James
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Correspondence to Thomas S. Griffith.

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James, B.R., Brincks, E.L., Kucaba, T.A. et al. Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells. Cancer Immunol Immunother 63, 685–697 (2014). https://doi.org/10.1007/s00262-014-1548-5

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