CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine

Alberto Comes, Ombretta Rosso, Anna Maria Orengo, Emma Di Carlo, Carlo Sorrentino, Raffaella Meazza, Tiziana Piazza, Barbara Valzasina, Patrizia Nanni, Mario P. Colombo, Silvano Ferrini

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Abstract

IL-21 is an IL-2-like cytokine, signaling through a specific IL-21R and the IL-2R γ-chain. Because the TS/A mammary adenocarcinoma cells genetically modified to secrete IL-21 (TS/A-IL-21) are strongly immunogenic in syngeneic mice, we analyzed their application as vaccine. In mice bearing TS/A-parental cell (pc) micrometastases, vaccination with irradiated TS/A-IL-21 cells significantly increased the animal life span, but cured only 17% of mice. Spleen cells from cured mice developed CTL activity and produced IFN-γ in response to stimulation by the AH1 epitope of the gp70env Ag of TS/A-pc. We tested whether the low therapeutic outcome might be due to CD4 +CD25+ regulatory T cells (Treg) present in TS/A-pc tumors and draining lymph nodes and whether IL-21 had any effect on these cells. Indeed, CD4+CD25+ cells suppressed IFN-γ production by splenocytes from immune mice in response to stimulation by the AH1 peptide. Low concentrations of IL-21 (10 ng/ml) failed to reverse the inhibitory activity of CD4+CD25+ cells in an allogeneic MLR, whereas 60 ng/ml rIL-21 partially restored responder T cell proliferation. IL-21R expression on CD25- lymphocytes suggested that IL-21 could be more effective in mice depleted of CD25+ cells. Depletion of Treg cells by a single dose of anti-CD25 mAb combined with TS/A-IL-21 cell vaccine cured >70% of mice bearing micrometastases, whereas anti-CD25 mAb treatment alone had no effect. Successful combined immunotherapy required NK cells, CD8+ T cells, and IFN-γ. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25+ cell depletion.

Original languageEnglish
Pages (from-to)1750-1758
Number of pages9
JournalJournal of Immunology
Volume176
Issue number3
Publication statusPublished - Feb 1 2006

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Neoplasm Micrometastasis
Regulatory T-Lymphocytes
Immunotherapy
Vaccines
interleukin-21
T-Lymphocytes
Natural Killer Cells
Interleukin-10
Interleukin-2
Epitopes
Vaccination
Adenocarcinoma
Breast
Spleen
Lymph Nodes

ASJC Scopus subject areas

  • Immunology

Cite this

Comes, A., Rosso, O., Orengo, A. M., Di Carlo, E., Sorrentino, C., Meazza, R., ... Ferrini, S. (2006). CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. Journal of Immunology, 176(3), 1750-1758.

CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. / Comes, Alberto; Rosso, Ombretta; Orengo, Anna Maria; Di Carlo, Emma; Sorrentino, Carlo; Meazza, Raffaella; Piazza, Tiziana; Valzasina, Barbara; Nanni, Patrizia; Colombo, Mario P.; Ferrini, Silvano.

In: Journal of Immunology, Vol. 176, No. 3, 01.02.2006, p. 1750-1758.

Research output: Contribution to journalArticle

Comes, A, Rosso, O, Orengo, AM, Di Carlo, E, Sorrentino, C, Meazza, R, Piazza, T, Valzasina, B, Nanni, P, Colombo, MP & Ferrini, S 2006, 'CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine', Journal of Immunology, vol. 176, no. 3, pp. 1750-1758.
Comes, Alberto ; Rosso, Ombretta ; Orengo, Anna Maria ; Di Carlo, Emma ; Sorrentino, Carlo ; Meazza, Raffaella ; Piazza, Tiziana ; Valzasina, Barbara ; Nanni, Patrizia ; Colombo, Mario P. ; Ferrini, Silvano. / CD25+ regulatory T cell depletion augments immunotherapy of micrometastases by an IL-21-secreting cellular vaccine. In: Journal of Immunology. 2006 ; Vol. 176, No. 3. pp. 1750-1758.
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abstract = "IL-21 is an IL-2-like cytokine, signaling through a specific IL-21R and the IL-2R γ-chain. Because the TS/A mammary adenocarcinoma cells genetically modified to secrete IL-21 (TS/A-IL-21) are strongly immunogenic in syngeneic mice, we analyzed their application as vaccine. In mice bearing TS/A-parental cell (pc) micrometastases, vaccination with irradiated TS/A-IL-21 cells significantly increased the animal life span, but cured only 17{\%} of mice. Spleen cells from cured mice developed CTL activity and produced IFN-γ in response to stimulation by the AH1 epitope of the gp70env Ag of TS/A-pc. We tested whether the low therapeutic outcome might be due to CD4 +CD25+ regulatory T cells (Treg) present in TS/A-pc tumors and draining lymph nodes and whether IL-21 had any effect on these cells. Indeed, CD4+CD25+ cells suppressed IFN-γ production by splenocytes from immune mice in response to stimulation by the AH1 peptide. Low concentrations of IL-21 (10 ng/ml) failed to reverse the inhibitory activity of CD4+CD25+ cells in an allogeneic MLR, whereas 60 ng/ml rIL-21 partially restored responder T cell proliferation. IL-21R expression on CD25- lymphocytes suggested that IL-21 could be more effective in mice depleted of CD25+ cells. Depletion of Treg cells by a single dose of anti-CD25 mAb combined with TS/A-IL-21 cell vaccine cured >70{\%} of mice bearing micrometastases, whereas anti-CD25 mAb treatment alone had no effect. Successful combined immunotherapy required NK cells, CD8+ T cells, and IFN-γ. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25+ cell depletion.",
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AU - Di Carlo, Emma

AU - Sorrentino, Carlo

AU - Meazza, Raffaella

AU - Piazza, Tiziana

AU - Valzasina, Barbara

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AU - Colombo, Mario P.

AU - Ferrini, Silvano

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