Co-introduced functional CCR2 potentiates in vivo anti-lung cancer functionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor.
Co-introduced functional CCR2 potentiates in vivo anti-lung cancer functionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor.
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DOI：
10.1371/journal.pone.0056820
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yasukawa M
中科院分区：
文献类型：
--
作者：
Asai H;Fujiwara H;An J;Ochi T;Miyazaki Y;Nagai K;Okamoto S;Mineno J;Kuzushima K;Shiku H;Inoue H;Yasukawa M
尽管T细胞基因修饰表达肿瘤相关抗原特异性T细胞受体(TCR)或嵌合抗原受体(CAR)已被临床证明是有希望的，但基于T细胞的重定向过继治疗仍有提高临床疗效的空间。为了利用体外扩增的肿瘤反应性T细胞达到更客观的临床反应，输注的T细胞需要表现出足够的肿瘤局部浸润。人类肺癌细胞表达肿瘤抗原Wilms‘s肿瘤基因产物1(WT1)和炎性趋化因子CCL2。然而，CCL2的相关受体CCR2在活化的T淋巴细胞上很少表达。以同时表达CCL2和WT1mRNA的人肺癌细胞系LK79为靶细胞。对正常CD8+T细胞进行逆转录病毒修饰，表达CCR2和HLA-A*2402限制性的TCR，并以WT1235-243为效应物。体外和体内检测了这些效应细胞对LK79细胞的抗肿瘤功能。最后研究了CCL2对效应细胞介导的WT1表位反应性TCR信号的影响。导入的CCR2在体外和体内用基因修饰的Jurkat细胞和人CD3+T细胞进行了功能验证。双基因修饰的CD3+T细胞在体内外成功地显示了趋化CCL2的肿瘤转移和对LK79细胞的杀伤活性。在双基因修饰的Jurkat/MA细胞中，CCl2通过相关荧光素酶的产生增强WT1表位反应性TcR信号，表达荧光素酶和WT1特异性TcR，CCl2还剂量依赖地增强这些双基因修饰的CD3+T细胞介导的WT1表位反应性干扰素γ的产生和CD107a的表达。CCL2/CCR2轴的引入成功地增强了CD8+T细胞的体内抗肺癌活性，CD8+T细胞表达WT1特异性TCR和CCR2不仅通过CCL2趋化肿瘤转移，而且通过CCL2增强WT1应答。
Although gene-modification of T cells to express tumor-related antigen-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) has clinically proved promise, there still remains room to improve the clinical efficacy of re-directed T-cell based antitumor adoptive therapy. In order to achieve more objective clinical responses using ex vivo-expanded tumor-responsive T cells, the infused T cells need to show adequate localized infiltration into the tumor. Human lung cancer cells variously express a tumor antigen, Wilms' Tumor gene product 1 (WT1), and an inflammatory chemokine, CCL2. However, CCR2, the relevant receptor for CCL2, is rarely expressed on activated T-lymphocytes. A HLA-A2402+ human lung cancer cell line, LK79, which expresses high amounts of both CCL2 and WT1 mRNA, was employed as a target. Normal CD8+ T cells were retrovirally gene-modified to express both CCR2 and HLA-A*2402-restricted and WT1235–243 nonapeptide-specific TCR as an effector. Anti-tumor functionality mediated by these effector cells against LK79 cells was assessed both in vitro and in vivo. Finally the impact of CCL2 on WT1 epitope-responsive TCR signaling mediated by the effector cells was studied. Introduced CCR2 was functionally validated using gene-modified Jurkat cells and human CD3+ T cells both in vitro and in vivo. Double gene-modified CD3+ T cells successfully demonstrated both CCL2-tropic tumor trafficking and cytocidal reactivity against LK79 cells in vitro and in vivo. CCL2 augmented the WT1 epitope-responsive TCR signaling shown by relevant luciferase production in double gene-modified Jurkat/MA cells to express luciferase and WT1-specific TCR, and CCL2 also dose-dependently augmented WT1 epitope-responsive IFN-γ production and CD107a expression mediated by these double gene-modifiedCD3+ T cells. Introduction of the CCL2/CCR2 axis successfully potentiated in vivo anti-lung cancer reactivity mediated by CD8+ T cells double gene-modified to express WT1-specific TCR and CCR2 not only via CCL2-tropic tumor trafficking, but also CCL2-enhanced WT1-responsiveness.
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DOI：
10.1084/jem.20031462
发表时间：
2004-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Metelitsa LS;Wu HW;Wang H;Yang Y;Warsi Z;Asgharzadeh S;Groshen S;Wilson SB;Seeger RC
通讯作者：
Seeger RC
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
7.4
作者：
Berencsi K;Rani P;Zhang T;Gross L;Mastrangelo M;Meropol NJ;Herlyn D;Somasundaram R
通讯作者：
Somasundaram R
剖析CCR2-CCL2轴在肿瘤存活和血管生成中的自分泌和旁分泌作用。
影响因子：
3.7
作者：
Izhak L;Wildbaum G;Jung S;Stein A;Shaked Y;Karin N
通讯作者：
Karin N
影响因子：
20.3
作者：
Louis, Chrystal U.;Savoldo, Barbara;Brenner, Malcolm K.
通讯作者：
Brenner, Malcolm K.