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

被引:81
作者
Comes, A
Rosso, O
Orengo, AM
Di Carlo, E
Sorrentino, C
Meazza, R
Piazza, T
Valzasina, B
Nanni, P
Colombo, MP
Ferrini, S
机构
[1] Ist Nazl Ric Canc, I-16132 Genoa, Italy
[2] Univ G DAnnunzio, Sez Anat Patol, Dipartimento Oncol & Neurosci, Chieti, Italy
[3] Fdn Univ G Dannunzio, Aging Res Ctr, Chieti, Italy
[4] Ist Giannina Gaslini, I-16148 Genoa, Italy
[5] Ist Nazl Tumori, I-20133 Milan, Italy
[6] Univ Bologna, Dipartimento Patol Sperimentale, Sez Cancerol, I-40126 Bologna, Italy
关键词
D O I
10.4049/jimmunol.176.3.1750
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
IL-21 is an IL-2-like cytokine, signaling through a specific IL-21R and the IL-2R gamma-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-gamma 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-gamma 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-gamma. In conclusion, immunotherapy of micrometastases by an IL-21-based cellular vaccine is strongly potentiated by CD25(+) cell depletion.
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页码:1750 / 1758
页数:9
相关论文
共 53 条
  • [1] Cutting edge:: The common γ-chain is an indispensable subunit of the IL-21 receptor complex
    Asao, H
    Okuyama, C
    Kumaki, S
    Ishii, N
    Tsuchiya, S
    Foster, D
    Sugamura, K
    [J]. JOURNAL OF IMMUNOLOGY, 2001, 167 (01) : 1 - 5
  • [2] Interleukin-2: Clinical applications
    Atkins, MB
    [J]. SEMINARS IN ONCOLOGY, 2002, 29 (03) : 12 - 17
  • [3] CD4+/CD25+ regulatory cells inhibit activation of tumor-primed CD4+ T cells with IFN-γ-dependent antiangiogenic activity, as well as long-lasting tumor immunity elicited by peptide vaccination
    Casares, N
    Arribillaga, L
    Sarobe, P
    Dotor, J
    de Cerio, ALD
    Melero, I
    Prieto, J
    Borrás-Cuesta, F
    Lasarte, JJ
    [J]. JOURNAL OF IMMUNOLOGY, 2003, 171 (11) : 5931 - 5939
  • [4] Cavallo F, 1999, CANCER RES, V59, P414
  • [5] Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3
    Chen, WJ
    Jin, WW
    Hardegen, N
    Lei, KJ
    Li, L
    Marinos, N
    McGrady, G
    Wahl, SM
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (12) : 1875 - 1886
  • [6] Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
    Curiel, TJ
    Coukos, G
    Zou, LH
    Alvarez, X
    Cheng, P
    Mottram, P
    Evdemon-Hogan, M
    Conejo-Garcia, JR
    Zhang, L
    Burow, M
    Zhu, Y
    Wei, S
    Kryczek, I
    Daniel, B
    Gordon, A
    Myers, L
    Lackner, A
    Disis, ML
    Knutson, KL
    Chen, LP
    Zou, WP
    [J]. NATURE MEDICINE, 2004, 10 (09) : 942 - 949
  • [7] MULTIPLE DEFECTS OF IMMUNE CELL-FUNCTION IN MICE WITH DISRUPTED INTERFERON-GAMMA GENES
    DALTON, DK
    PITTSMEEK, S
    KESHAV, S
    FIGARI, IS
    BRADLEY, A
    STEWART, TA
    [J]. SCIENCE, 1993, 259 (5102) : 1739 - 1742
  • [8] IL-21 induces tumor rejection by specific CTL and IFN-γ-dependent CXC chemokines in syngeneic mice
    Di Carlo, E
    Comes, A
    Orengo, AM
    Rosso, O
    Meazza, R
    Musiani, P
    Colombo, MP
    Ferrini, S
    [J]. JOURNAL OF IMMUNOLOGY, 2004, 172 (03) : 1540 - 1547
  • [9] Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity
    Emens, LA
    Reilly, RT
    Jaffee, EM
    [J]. ENDOCRINE-RELATED CANCER, 2005, 12 (01) : 1 - 17
  • [10] Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells (Reprinted from vol 4, pg 330-336, 2003)
    Fontenot, Jason D.
    Gavin, Marc A.
    Rudensky, Alexander Y.
    [J]. JOURNAL OF IMMUNOLOGY, 2017, 198 (03) : 986 - 992