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肿瘤特异性产生 IL-9 的 CD8+Tc9 细胞比 I 型细胞毒性 Tc1 细胞更适合用于癌症的过继免疫治疗。

Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers.

机构信息

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.

出版信息

Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2265-70. doi: 10.1073/pnas.1317431111. Epub 2014 Jan 27.


DOI:10.1073/pnas.1317431111
PMID:24469818
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3926063/
Abstract

Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Rα(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers.

摘要

由于细胞因子引发信号会引导 CD8(+)T 细胞获得独特的表型,从而影响其介导特定免疫反应的能力,因此我们通过 Th9 极化条件的诱导产生了偏向于分泌白细胞介素-9(IL-9)的 CD8(+)T(Tc9)细胞。与 I 型 CD8(+)细胞毒性 T(Tc1)细胞相比,Tc9 细胞分泌的细胞因子不同,体外细胞毒性较低,但令人惊讶的是,在 OT-I/B16-OVA 和 Pmel-1/B16 黑色素瘤模型中,它们对晚期肿瘤引发了更强的抗肿瘤反应。在过继转移后,Tc9 细胞持续存在时间更长,并分化为产生 IFN-γ 和颗粒酶 B(GrzB)的细胞毒性 Tc1 样效应细胞。表型分析显示,过继转移的 Tc9 细胞分泌 IL-2,且 KLRG-1(低)和 IL-7Rα(高),表明它们获得了“年轻”表型的特征或成为具有自我更新能力的长期存活细胞。我们的研究结果还表明,Tc9 介导的治疗效果在很大程度上取决于体内的 IL-9 产生。这些发现对改善基于 CD8(+)T 细胞的癌症过继免疫疗法具有临床意义。

相似文献

[1]
Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers.

Proc Natl Acad Sci U S A. 2014-1-27

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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[10]
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本文引用的文献

[1]
Utilizing T9 cells as a novel therapeutic strategy for malignancies.

Oncoimmunology. 2013-3-1

[2]
Th9 cells: differentiation and disease.

Immunol Rev. 2013-3

[3]
Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms.

J Immunol. 2013-1-11

[4]
T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment.

Curr Opin Immunol. 2013-1-6

[5]
Tc9 cells, a new subset of CD8(+) T cells, support Th2-mediated airway inflammation.

Eur J Immunol. 2013-1-31

[6]
Th9 cells promote antitumor immune responses in vivo.

J Clin Invest. 2012-10-15

[7]
Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells.

Nat Med. 2012-7-8

[8]
Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

N Engl J Med. 2012-6-2

[9]
TGF-β converts apoptotic stimuli into the signal for Th9 differentiation.

J Immunol. 2012-3-28

[10]
Adoptive immunotherapy for cancer: harnessing the T cell response.

Nat Rev Immunol. 2012-3-22

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