Local secretion of IL-12 augments the therapeutic impact of dendritic celletumor cell fusion vaccination

Chunrui Tan, Jens Dannull, Smita K. Nair, Enyu Ding, Douglas Tyler, Scott K. Pruitt, Walter T. Lee

Research output: Contribution to journalArticle

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Abstract

Background: The development of dendritic cell (DC)etumor fusion vaccines is a promising approach in cancer immunotherapy. Using fusion vaccines allows a broad spectrum of known and unidentified tumor-associated antigens to be presented in the context of MHC class I and class II molecules, with potent co-stimulation provided by the DCs. Although DC etumor fusion cells are immunogenic, murine studies have shown that effective immunotherapy requires a third signal, which can be provided by exogenous interleukin 12 (IL-12). Unfortunately, systemic administration of IL-12 induces severe toxicity in cancer patients, potentially precluding clinical use of this cytokine to augment fusion vaccine efficacy. To overcome this limitation, we developed a novel approach in which DCetumor fusion cells locally secrete IL-12, then evaluated the effectiveness of this approach in a murine B16 melanoma model. Materials and methods: Tumor cells were stably transduced to secrete murine IL-12p70. These tumor cells were then electrofused to DC to form DCetumor heterokaryons. These cells were used to treat established B16 pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon rank sum test. Interferon g enzyme-linked immunosorbent spot assay was performed on splenocytes from treated mice. Results: We show that vaccination with DCs fused to syngeneic melanoma cells that stably express murine IL-12p70 significantly reduces counts of established lung metastases in treated animals when compared with DCetumor alone (P = 0.029). Interferon g enzymelinked immunosorbent spot assays suggest that this antitumor response is mediated by CD4+ T cells, in the absence of a tumor-specific CD8+ T cell response, and that the concomitant induction of antitumor CD4+ and CD8+ T cell responses required exogenous IL-12. Conclusions: This study is, to the best of our knowledge, the first report that investigates the impact of local secretion of IL-12 on antitumor immunity induced by a DCetumor fusion cell vaccine in a melanoma model and may aid the rational design of future clinical trials.

Original languageEnglish (US)
Pages (from-to)904-911
Number of pages8
JournalJournal of Surgical Research
Volume185
Issue number2
DOIs
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Cell Fusion
Interleukin-12
Dendritic Cells
Vaccination
Vaccines
Neoplasms
Nonparametric Statistics
Neoplasm Metastasis
T-Lymphocytes
Immunotherapy
Interferons
Melanoma
Therapeutics
Lung
Immunosorbents
Experimental Melanomas
Neoplasm Antigens
Immunity
Enzyme-Linked Immunosorbent Assay
Clinical Trials

Keywords

  • Animal model
  • Dendritic cell
  • Electrofusion
  • ELISPOT
  • Fusion hybrids
  • Immunotherapy
  • Interleukin 12
  • Melanoma
  • T cell
  • Vaccine

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)

Cite this

Local secretion of IL-12 augments the therapeutic impact of dendritic celletumor cell fusion vaccination. / Tan, Chunrui; Dannull, Jens; Nair, Smita K.; Ding, Enyu; Tyler, Douglas; Pruitt, Scott K.; Lee, Walter T.

In: Journal of Surgical Research, Vol. 185, No. 2, 12.2013, p. 904-911.

Research output: Contribution to journalArticle

Tan, Chunrui ; Dannull, Jens ; Nair, Smita K. ; Ding, Enyu ; Tyler, Douglas ; Pruitt, Scott K. ; Lee, Walter T. / Local secretion of IL-12 augments the therapeutic impact of dendritic celletumor cell fusion vaccination. In: Journal of Surgical Research. 2013 ; Vol. 185, No. 2. pp. 904-911.
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AU - Lee, Walter T.

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AB - Background: The development of dendritic cell (DC)etumor fusion vaccines is a promising approach in cancer immunotherapy. Using fusion vaccines allows a broad spectrum of known and unidentified tumor-associated antigens to be presented in the context of MHC class I and class II molecules, with potent co-stimulation provided by the DCs. Although DC etumor fusion cells are immunogenic, murine studies have shown that effective immunotherapy requires a third signal, which can be provided by exogenous interleukin 12 (IL-12). Unfortunately, systemic administration of IL-12 induces severe toxicity in cancer patients, potentially precluding clinical use of this cytokine to augment fusion vaccine efficacy. To overcome this limitation, we developed a novel approach in which DCetumor fusion cells locally secrete IL-12, then evaluated the effectiveness of this approach in a murine B16 melanoma model. Materials and methods: Tumor cells were stably transduced to secrete murine IL-12p70. These tumor cells were then electrofused to DC to form DCetumor heterokaryons. These cells were used to treat established B16 pulmonary metastases. Enumeration of these metastases was performed and compared between experimental groups using Wilcoxon rank sum test. Interferon g enzyme-linked immunosorbent spot assay was performed on splenocytes from treated mice. Results: We show that vaccination with DCs fused to syngeneic melanoma cells that stably express murine IL-12p70 significantly reduces counts of established lung metastases in treated animals when compared with DCetumor alone (P = 0.029). Interferon g enzymelinked immunosorbent spot assays suggest that this antitumor response is mediated by CD4+ T cells, in the absence of a tumor-specific CD8+ T cell response, and that the concomitant induction of antitumor CD4+ and CD8+ T cell responses required exogenous IL-12. Conclusions: This study is, to the best of our knowledge, the first report that investigates the impact of local secretion of IL-12 on antitumor immunity induced by a DCetumor fusion cell vaccine in a melanoma model and may aid the rational design of future clinical trials.

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