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Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice.

ABSTRACT: Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administration of Cl-IB-MECA (20 ng/mouse) inhibited tumor growth compared with the control group and significantly improved mouse survival. This was associated with the release of Th1-type cytokines and a greater influx of mature Langerin+ dendritic cells (LCs) into the tumor microenvironment. CD8+ T cells treated with Cl-IB-MECA released TNF-? which plays a critical role in the therapeutic efficacy of these cells when injected to mice. Indeed, neutralization of TNF-? by a specific monoclonal Ab significantly blocked the anti-tumor activity of Cl-IB-MECA-treated T cells. This was due to the reduction in levels of cytotoxic cytokines and the presence of fewer LCs. In conclusion, these studies reveal that ex vivo treatment with Cl-IB-MECA improves CD8+ T cell adoptive immunotherapy for melanoma in a TNF-?-dependent manner.

SUBMITTER: Montinaro A

PROVIDER: S-EPMC3454429 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice.

Montinaro Antonella A Forte Giovanni G Sorrentino Rosalinda R Luciano Antonio A Palma Giuseppe G Arra Claudio C Adcock Ian M IM Pinto Aldo A Morello Silvana S

PloS one 20120924 9

Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administra ...[more]

PMID: 23028986

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Project description:IL-2 and IL-21 are closely related cytokines that might have arisen by gene duplication. Both cytokines promote the function of effector CD8+ T cells, but their distinct effects on antigen-driven differentiation of naÃ¯ve CD8+ T cells into effector CD8+ T cells are not clearly understood. We found that antigen-induced expression of eomesodermin and maturation of naÃ¯ve CD8+ T cells into granzyme B and CD44 expressing effector CD8+ T cells was enhanced by IL-2, but, unexpectedly, suppressed by IL-21. Furthermore, IL-21 repressed expression of IL-2Ra and inhibited IL-2-mediated acquisition of a cytolytic CD8+ T cell phenotype. Despite its inhibitory effects, IL-21 did not induce anergy, but instead potently enhanced the capacity of cells to mediate tumor regression upon adoptive transfer. In contrast, IL-2, surprisingly, impaired the subsequent anti-tumor function of transferred cells. Gene expression studies revealed a distinct IL-21-program that was characterized phenotypically by increased expression of L-selectin and functionally by enhanced anti-tumor immunity that was not reversed by secondary in vitro stimulation with antigen and IL-2. Thus, the efficacy of CD8+ T cells for adoptive immunotherapy can be influenced by opposing differentiation programs conferred by IL-2 and IL-21, a finding with important implications for the development of cellular cancer therapies. Two-condition experiment: Cytokine-exposed t-cells subsequentially restimulated without cytokine vs. control t-cells without cytokine subsquentially restimulated without cytokine. 3 independent experiments - 1 with experimental RNA labeled with Cy5, control with Cy3, and 2 with dyes-swapped Keywords: Cytokine exposure comparison Comparitive analysis of cytokine effects on lymphocyte gene expression. GSM265712.gpr (S89_1_IL2_0.gpr): Cy3 - control, Cy5 - experimental GSM265713.gpr (S90_1_IL15_0.gpr): Cy3 - control, Cy5 - experimental GSM265714.gpr (S91_1_IL21_0.gpr): Cy3 - control, Cy5 - experimental GSM265715.gpr (S27_2_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265716.gpr (S29_2_0_IL15.gpr): Cy3 - experimental, Cy5 - control GSM265717.gpr (S30_2_0_IL21.gpr): Cy3 - experimental, Cy5 - control GSM265718.gpr (S31_3_0_IL2.gpr): Cy3 - experimental, Cy5 - control GSM265719.gpr (S33_3_0_IL15.gpr): Cy3 - experimental, Cy5 - control

Dataset Information

Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice.

Publications

Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice.

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