CD40 ligand is essential for generation of specific cytotoxic T cell responses in RNA-pulsed dendritic cell immunotherapy

Mark W. Onaitis, Matthew F. Kalady, Sirisha Emani, Zeinab Abdel-Wahab, Douglas Tyler, Scott K. Pruitt

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background. Dendritic cell (DC)-based immunotherapy is a promising form of adjuvant therapy for high-risk tumors. DCs transfected with tumor-associated antigens are capable of stimulating antigen-specific T cells, but cytolytic responses have been disappointing. Activation of DC surface CD40 influences DC cytokine production, particularly that of interleukin (IL)-12, which favors a Th1 (cytotoxic) helper T cell response. This study evaluated the effects of exogenous soluble CD40 ligand (sCD40L) on RNA-transfected DC preparations and their subsequent ability to generate antimelanoma cytolytic T cells. Methods. Human monocyte-derived DCs were cultured and transfected with mRNA encoding full-length melanoma-associated antigen, Mart-1, and matured with and without sCD40L. DC IL-12 secretion and the ability to stimulate naïve T cells were assessed by enzyme-linked immunosorbent assay (ELISA), tetramer analysis, Elispot, and 51Cr release assay. Results. Mature DCs stimulated with sCD40L secreted higher levels of IL-12 compared with immature DCs and DCs matured without sCD40L (P < .001). DCs treated with sCD40L generated a greater number of antigen-specific T cells (P < .05) by tetramer and Elispot analyses, and yielded specific T cells with significant cytotoxicity against HLA-matched melanoma cell lines. Conclusions. CD40L augments DC IL-12 secretion and is essential to potentiate specific antimelanoma cytolytic responses stimulated by the Mart-1 antigen, sCD40L should be considered a crucial adjuvant in DC preparations for RNA-based DC vaccine therapies.

Original languageEnglish (US)
Pages (from-to)300-305
Number of pages6
JournalSurgery
Volume134
Issue number2
DOIs
StatePublished - Aug 1 2003
Externally publishedYes

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CD40 Ligand
Immunotherapy
Dendritic Cells
RNA
T-Lymphocytes
Interleukin-12
Antigens
Melanoma-Specific Antigens
Active Immunotherapy
Neoplasm Antigens
Cell- and Tissue-Based Therapy
Helper-Inducer T-Lymphocytes
Monocytes
Melanoma
Enzyme-Linked Immunosorbent Assay
Cytokines
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Surgery

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CD40 ligand is essential for generation of specific cytotoxic T cell responses in RNA-pulsed dendritic cell immunotherapy. / Onaitis, Mark W.; Kalady, Matthew F.; Emani, Sirisha; Abdel-Wahab, Zeinab; Tyler, Douglas; Pruitt, Scott K.

In: Surgery, Vol. 134, No. 2, 01.08.2003, p. 300-305.

Research output: Contribution to journalArticle

Onaitis, Mark W. ; Kalady, Matthew F. ; Emani, Sirisha ; Abdel-Wahab, Zeinab ; Tyler, Douglas ; Pruitt, Scott K. / CD40 ligand is essential for generation of specific cytotoxic T cell responses in RNA-pulsed dendritic cell immunotherapy. In: Surgery. 2003 ; Vol. 134, No. 2. pp. 300-305.
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AU - Tyler, Douglas

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N2 - Background. Dendritic cell (DC)-based immunotherapy is a promising form of adjuvant therapy for high-risk tumors. DCs transfected with tumor-associated antigens are capable of stimulating antigen-specific T cells, but cytolytic responses have been disappointing. Activation of DC surface CD40 influences DC cytokine production, particularly that of interleukin (IL)-12, which favors a Th1 (cytotoxic) helper T cell response. This study evaluated the effects of exogenous soluble CD40 ligand (sCD40L) on RNA-transfected DC preparations and their subsequent ability to generate antimelanoma cytolytic T cells. Methods. Human monocyte-derived DCs were cultured and transfected with mRNA encoding full-length melanoma-associated antigen, Mart-1, and matured with and without sCD40L. DC IL-12 secretion and the ability to stimulate naïve T cells were assessed by enzyme-linked immunosorbent assay (ELISA), tetramer analysis, Elispot, and 51Cr release assay. Results. Mature DCs stimulated with sCD40L secreted higher levels of IL-12 compared with immature DCs and DCs matured without sCD40L (P < .001). DCs treated with sCD40L generated a greater number of antigen-specific T cells (P < .05) by tetramer and Elispot analyses, and yielded specific T cells with significant cytotoxicity against HLA-matched melanoma cell lines. Conclusions. CD40L augments DC IL-12 secretion and is essential to potentiate specific antimelanoma cytolytic responses stimulated by the Mart-1 antigen, sCD40L should be considered a crucial adjuvant in DC preparations for RNA-based DC vaccine therapies.

AB - Background. Dendritic cell (DC)-based immunotherapy is a promising form of adjuvant therapy for high-risk tumors. DCs transfected with tumor-associated antigens are capable of stimulating antigen-specific T cells, but cytolytic responses have been disappointing. Activation of DC surface CD40 influences DC cytokine production, particularly that of interleukin (IL)-12, which favors a Th1 (cytotoxic) helper T cell response. This study evaluated the effects of exogenous soluble CD40 ligand (sCD40L) on RNA-transfected DC preparations and their subsequent ability to generate antimelanoma cytolytic T cells. Methods. Human monocyte-derived DCs were cultured and transfected with mRNA encoding full-length melanoma-associated antigen, Mart-1, and matured with and without sCD40L. DC IL-12 secretion and the ability to stimulate naïve T cells were assessed by enzyme-linked immunosorbent assay (ELISA), tetramer analysis, Elispot, and 51Cr release assay. Results. Mature DCs stimulated with sCD40L secreted higher levels of IL-12 compared with immature DCs and DCs matured without sCD40L (P < .001). DCs treated with sCD40L generated a greater number of antigen-specific T cells (P < .05) by tetramer and Elispot analyses, and yielded specific T cells with significant cytotoxicity against HLA-matched melanoma cell lines. Conclusions. CD40L augments DC IL-12 secretion and is essential to potentiate specific antimelanoma cytolytic responses stimulated by the Mart-1 antigen, sCD40L should be considered a crucial adjuvant in DC preparations for RNA-based DC vaccine therapies.

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