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Comparison of AAV/IL-7 autocrine (T cell) versus paracrine (DC) gene delivery for enhancing CTL stimulation and function

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Abstract

Adoptive transfer of antigen-specific cytotoxic T lymphocyte (CTL) into patients holds promise in treating cancer. Such anti-cancer CTL are stimulated by professional antigen-presenting dendritic cells (DC). We hypothesize the gene delivery of various Th1-response cytokines, such as interleukin 7 (IL-7), should further enhance CTL stimulation and activity. However, the issue as to which cell type, DC (paracrine) or the T cell (autocrine), should express a particular Th1 cytokine gene for optimal CTL stimulation has never been addressed. We used adeno-associated virus-2 (AAV) to compare delivery of IL-7 and IL-2 genes into DC or T cells and to exogenous commercial cytokines for generating robust carcinoembryonic antigen (CEA)-specific CTL. AAV/IL-7 transduction of T cells (autocrine delivery) generated CTL with the highest killing capability. Consistent with this, AAV/IL-7 delivery generated T cell populations with the highest proliferation, highest interferon γ expression, highest CD8(+):CD4(+) ratio, highest CD8(+), CD69(+) levels, and lowest CD4(+), CD25(+) (Treg) levels. These data are consistent with higher killing by the AAV/IL-7-altered CTL. These data strongly suggest that IL-7 autocrine gene delivery is optimal for CTL generation. These data also suggest Th1 cytokine autocrine versus paracrine delivery is an important issue for immuno-gene therapy and uncovers new questions into cytokine mechanism of action.

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Abbreviations

AAV:

Adeno-associated virus

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cells

GM-CSF:

Granulocyte–macrophage colony stimulating factor

IL-7:

Interleukin 7

exo:

Exogenous

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Acknowledgments

This study was funded by the Fashion Footwear of New York (FFANY/QVC) through the Arkansas Breast Cancer Foundation. Drs. You and Liu contributed equally to this study.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Arkansas for Medical Sciences, Slot 532, 4301 West Markham St., Little Rock, AR, 72205, USA

    Chang-Xuan You, Yong Liu, Min Shi, Maohua Cao & Paul L. Hermonat

  2. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Chang-Xuan You, Min Shi & Rong-Cheng Luo

  3. Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA

    Yong Liu & Paul L. Hermonat

Authors
  1. Chang-Xuan You
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  2. Yong Liu
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  3. Min Shi
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  4. Maohua Cao
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  5. Rong-Cheng Luo
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  6. Paul L. Hermonat
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Corresponding author

Correspondence to Paul L. Hermonat.

Additional information

C.-X. You and Y. Liu contributed equally to this manuscript.

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You, CX., Liu, Y., Shi, M. et al. Comparison of AAV/IL-7 autocrine (T cell) versus paracrine (DC) gene delivery for enhancing CTL stimulation and function. Cancer Immunol Immunother 59, 779–787 (2010). https://doi.org/10.1007/s00262-009-0798-0

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  • DOI: https://doi.org/10.1007/s00262-009-0798-0

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