Marrow stromal cells for interleukin-2 delivery in cancer immunotherapy

被引:81
作者
Stagg, J
Lejeune, L
Paquin, A
Galipeau, J
机构
[1] McGill Univ, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Jewish Gen Hosp, Div Hematol Oncol, Montreal, PQ H3T 1E2, Canada
关键词
D O I
10.1089/104303404323142042
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Marrow stromal cells (MSCs) can be easily gene-modified and clonally expanded making them ideal candidates for transgenic cell therapy. However, recent reports suggest that MSCs possess immunosuppressive effects, which may limit their clinical applications. We investigated whether interleukin (IL)-2 gene-modified MSCs can be used to mount an effective immune response against the poorly immunogenic B16 melanoma model. We first show that primary MSCs mixed with B16 cells and injected subcutaneously in syngeneic recipients do not affect tumor growth. On the other hand, IL-2-producing MSCs mixed with B16 cells significantly delayed tumor growth in an IL-2 dose-dependent manner. Furthermore, we observed that matrix-embedded IL-2-producing MSCs injected in the vicinity of preestablished B16 tumors led to absence of tumor growth in 90% of treated mice (p < 0.001). We demonstrated that tumor-bearing mice treated with IL-2-producing MSCs developed CD8-mediated tumor-specific immunity and significantly delayed tumor growth of a B16 cell challenge (p < 0.05). In addition, treatment of cd8-/-, cd4-/- and beige mice revealed that CD8(+) and natural killer (NK) cells, but not CD4(+) cells, were required to achieve antitumor effect. In conclusion, MSCs can be exploited to deliver IL-2 and generate effective immune responses against melanoma in mice with normal immune systems.
引用
收藏
页码:597 / 608
页数:12
相关论文
共 40 条
  • [1] Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo
    Al-Khaldi, A
    Eliopoulos, N
    Martineau, D
    Lejeune, L
    Lachapelle, K
    Galipeau, J
    [J]. GENE THERAPY, 2003, 10 (08) : 621 - 629
  • [2] Origin of regulatory T cells with known specificity for antigen
    Apostolou, I
    Sarukhan, A
    Klein, L
    von Boehmer, H
    [J]. NATURE IMMUNOLOGY, 2002, 3 (08) : 756 - 763
  • [3] Aruga A, 1997, CANCER RES, V57, P3230
  • [4] CD8+ T cells rapidly acquire NK1.1 and NK cell-associated molecules upon stimulation in vitro and in vivo
    Assarsson, E
    Kambayashi, T
    Sandberg, JK
    Hong, S
    Taniguchi, M
    Van Kaer, L
    Ljunggren, HG
    Chambers, BJ
    [J]. JOURNAL OF IMMUNOLOGY, 2000, 165 (07) : 3673 - 3679
  • [5] Atkins MB, 2000, CANCER J SCI AM, V6, pS11
  • [6] Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo
    Bartholomew, A
    Patil, S
    Mackay, A
    Nelson, M
    Buyaner, D
    Hardy, W
    Mosca, J
    Sturgeon, C
    Siatskas, M
    Mahmud, N
    Ferrer, K
    Deans, R
    Moseley, A
    Hoffman, R
    Devine, SM
    [J]. HUMAN GENE THERAPY, 2001, 12 (12) : 1527 - 1541
  • [7] Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo
    Bartholomew, A
    Sturgeon, C
    Siatskas, M
    Ferrer, K
    McIntosh, K
    Patil, S
    Hardy, W
    Devine, S
    Ucker, D
    Deans, R
    Moseley, A
    Hoffman, R
    [J]. EXPERIMENTAL HEMATOLOGY, 2002, 30 (01) : 42 - 48
  • [8] Interleukin 2 gene therapy for prostate cancer: Phase I clinical trial and basic biology
    Belldegrun, A
    Tso, CL
    Zisman, A
    Naitoh, J
    Said, J
    Pantuck, AJ
    Hinkel, A
    de Kernion, J
    Figlin, R
    [J]. HUMAN GENE THERAPY, 2001, 12 (08) : 883 - 892
  • [9] IL-2 adenovector-transduced autologous tumor cells reduce antitumor immune responses in patients with neuroblastoma
    Bowman, L
    Grossmann, M
    Rill, D
    Brown, M
    Zhong, WY
    Alexander, B
    Leimig, T
    Coustan-Smith, E
    Campana, D
    Jenkins, J
    Woods, D
    Kitchingman, G
    Vanin, E
    Brenner, M
    [J]. BLOOD, 1998, 92 (06) : 1941 - 1949
  • [10] Transplantation of stromal cells transduced with the human IL3 gene to stimulate hematopoiesis in human fetal bone grafts in non-obese, diabetic severe combined immunodeficiency mice
    Brouard, N
    Chapel, A
    Neildez-Nguyen, TMA
    Granotier, C
    Khazaal, I
    Péault, B
    Thierry, D
    [J]. LEUKEMIA, 1998, 12 (07) : 1128 - 1135