期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 62, 期 8, 页码 1359-1368出版社
SPRINGER
DOI: 10.1007/s00262-013-1439-1
关键词
Natural killer cells; T cells; Proteasome inhibitor; TRAIL; Immunotherapy
资金
- Swedish Research Council
- Swedish Cancer Society
- European Research Council
- Karolinska Institutet
- Jeanssons Stiftelser
- Ake Wibergs Stiftelse
- Magnus Bergvalls Stiftelse
- Fredrik och Ingrid Thurings Stiftelse
- Stiftelsen Clas Groschinskys Minnesfond
- Swedish Society of Medicine
The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p < 0.0002) and T cell (p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 expression (p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p = 0.006), T cells (p < 0.0001) or b-AP15 alone (p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p a parts per thousand currency sign 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据