TCR gene-engineered T cell: Limited T cell activation and combined use of IL-15 and IL-21 ensure minimal differentiation and maximal antigen-specificity

被引:15
作者
Pouw, Nadine [1 ]
Treffers-Westerlaken, Elike [1 ]
Mondino, Anna [3 ]
Lamers, Cor [2 ]
Debets, Reno [1 ]
机构
[1] Erasmus MC Daniel Den Hoed Canc Ctr, Lab Expt Tumor Immunol, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands
[2] Erasmus MC Daniel Den Hoed Canc Ctr, Lab Clin Tumor Immunol, Dept Med Oncol, Rotterdam, Netherlands
[3] Ist San Raffaele Telethon Terapia Genica, Milan, Italy
关键词
Common-gamma cytokines; Primary T lymphocytes; Retroviral transduction; T cell activation; T cell differentiation; TCR transgenes; CLINICAL IMMUNOGENE THERAPY; SUPERIOR ANTITUMOR IMMUNITY; CANCER REGRESSION; SINGLE-CHAIN; RETROVIRAL TRANSDUCTION; ADOPTIVE IMMUNOTHERAPY; METASTATIC MELANOMA; LYMPHOCYTES; MEMORY; EXPRESSION;
D O I
10.1016/j.molimm.2010.02.022
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Clinical TCR gene therapy of melanoma represents a feasible and promising treatment rationale yet is currently challenged by objective response rates that stay behind those observed with conventional adoptive T cell therapy. Here, the phenotype and function of TCR-transduced T cells, considered to determine the efficacy of TCR gene therapy, were studied in relation to T cell activation and cytokine treatments. We observed that the lectin Concanavalin A (ConA), and to a lesser extent anti-CD3 and CD28 mAbs (soluble CD3/CD28), resulted in functional surface expression of the TCR alpha beta transgenes and enhanced fractions of CD62L(hi), CD44(lo) naive T cells. T cell functions and limited T cell differentiation were most significant when T cells were treated with a combination of IL-15 and IL-21 rather than IL-2. In comparison, anti-CD3 and CD28 mAbs coated to either latex or polystyrene beads (polystyrene or latex CD3/CD28) resulted in improved TCR expression levels and enhanced T cell differentiation irrespective of cytokine treatment, with effects most pronounced for polystyrene CD3/CD28.T cells demonstrated enhanced cytotoxic activity and IFN gamma production when activated with CD3/CD28 beads and treated with IL-15 and IL-21, but at the same time displayed non-specific T cell responses. In contrast, ConA and soluble CD3/CD28 activations resulted in antigen-specific T cell responses. In short, we show that retroviral TCR engineering of primary T cells benefits from activation with ConA or soluble CD3/CD28 rather than immobilized anti-CD3 and CD28 mAbs with respect to T cell differentiation and antigen-specificity of T cell responses. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1411 / 1420
页数:10
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