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过继转移后初始型和中枢记忆型来源的CD8效应细胞植入适应性及功能的比较

Comparison of naïve and central memory derived CD8 effector cell engraftment fitness and function following adoptive transfer.

作者信息

Wang Xiuli, Wong ChingLam W, Urak Ryan, Taus Ellie, Aguilar Brenda, Chang Wen-Chung, Mardiros Armen, Budde Lihua E, Brown Christine E, Berger Carolina, Forman Stephen J, Jensen Michael C

机构信息

Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center , Duarte, CA, USA.

Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.

出版信息

Oncoimmunology. 2015 Aug 20;5(1):e1072671. doi: 10.1080/2162402X.2015.1072671. eCollection 2016.

DOI:10.1080/2162402X.2015.1072671
PMID:26942092
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4760301/
Abstract

Human CD8 effector T cells derived from CD45ROCD62L precursors enriched for central memory (T) precursors retain the capacity to engraft and reconstitute functional memory upon adoptive transfer, whereas effectors derived from CD45ROCD62L precursors enriched for effector memory precursors do not. Here we sought to compare the engraftment fitness and function of CD8 effector T cells derived from CD45RACD62L precursors enriched for naïve and stem cell memory precursors (T) with that of T. We found that cytotoxic T cells (CTLs) derived from T transcribed higher levels of CD28, FOS, INFγ, Eomesodermin (Eomes), and lower levels of BCL2L11, maintained higher levels of phosphorylated AKT, and displayed enhanced sensitivity to the proliferative and anti-apoptotic effects of γ-chain cytokines compared to CTLs derived from T. Higher frequencies of CTLs derived from T retained CD28 expression and upon activation secreted higher levels of IL-2. In NOD/ IL-2RγC mice, CD8 T derived CTLs engrafted to higher frequencies in response to human IL-15 and mounted robust proliferative responses to an immunostimulatory vaccine. Similarly, CD8 T derived CD19CAR CTLs exhibited superior antitumor potency following adoptive transfer compared to their CD8 T derived counterparts. These studies support the use of T enriched cell products for adoptive therapy of cancer.

摘要

源自富含中枢记忆（T）前体的CD45ROCD62L前体的人CD8效应T细胞在过继转移后保留了植入并重建功能性记忆的能力，而源自富含效应记忆前体的CD45ROCD62L前体的效应T细胞则不具备这种能力。在这里，我们试图比较源自富含初始和干细胞记忆前体（T）的CD45RACD62L前体的CD8效应T细胞与T细胞的植入适应性和功能。我们发现，与源自T的细胞毒性T细胞（CTL）相比，源自T的CTL转录的CD28、FOS、INFγ、Eomesodermin（Eomes）水平更高，BCL2L11水平更低，维持更高水平的磷酸化AKT，并且对γ链细胞因子的增殖和抗凋亡作用表现出更高的敏感性。源自T的CTL中更高频率的细胞保留CD28表达，激活后分泌更高水平的IL-2。在NOD/IL-2RγC小鼠中，源自CD8 T的CTL在人IL-15刺激下以更高的频率植入，并对免疫刺激疫苗产生强烈的增殖反应。同样，与源自CD8 T的对应物相比，源自CD8 T的CD19CAR CTL在过继转移后表现出更强的抗肿瘤效力。这些研究支持使用富含T的细胞产品进行癌症的过继治疗。

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Comparison of naïve and central memory derived CD8 effector cell engraftment fitness and function following adoptive transfer.

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[2]
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[5]
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[8]
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本文引用的文献

[1]
Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy.

Mol Ther. 2015-4

[2]
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Cancer Immunol Res. 2014-9-11

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Immunity. 2014-7-17

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Immunity. 2014-7-17

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N Engl J Med. 2013-3-25

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Sci Transl Med. 2013-3-20

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J Clin Invest. 2013-1-2

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IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors.

Blood. 2012-11-15

[9]
Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale.

J Immunother. 2012

[10]
The stoichiometric production of IL-2 and IFN-γ mRNA defines memory T cells that can self-renew after adoptive transfer in humans.

Sci Transl Med. 2012-8-29

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