In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2.
In vitro migration of cytotoxic T lymphocyte derived from a colon carcinoma patient is dependent on CCL2 and CCR2.
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DOI：
10.1186/1479-5876-9-33
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发表时间：
2011-03-30
影响因子：
7.4
通讯作者：
Somasundaram R
中科院分区：
文献类型：
--
作者：
Berencsi K;Rani P;Zhang T;Gross L;Mastrangelo M;Meropol NJ;Herlyn D;Somasundaram R
结直肠癌（CRC）浸润T细胞与良好的预后相关。有一些迹象表明，趋化因子可能参与肿瘤的T细胞浸润。选择性调节肿瘤部位的趋化因子活性可以吸引免疫细胞，导致肿瘤生长抑制。在小鼠肿瘤模型系统中，使用趋化因子的基因治疗或施用抗体（Ab）-趋化因子融合蛋白提供了有效的免疫介导的肿瘤排斥，其由肿瘤部位的浸润T细胞介导。要为癌症患者开发这种免疫策略，必须确定参与T细胞向肿瘤细胞迁移的趋化因子及其受体。为了鉴定参与T细胞向CRC细胞迁移的趋化因子和趋化因子受体，我们使用了我们先前发表的三维器官型CRC培养系统。在24孔组织培养板中用一层与胶原基质混合的胎儿成纤维细胞开始器官型培养。将CRC细胞层置于成纤维细胞-胶原蛋白层的顶部，随后是胶原蛋白基质中的成纤维细胞分离层。将与胶原基质中的成纤维细胞混合的抗CRC特异性细胞毒性T淋巴细胞（CTL）置于分离层的顶部。过量的趋化因子配体（CCL）或针对趋化因子或趋化因子受体（CCR）的Ab用于迁移抑制测定以鉴定参与CTL迁移的趋化因子和受体。在T细胞层中包含过量的CCL 2或在胶原成纤维细胞的分离层中包含针对CCL 2的Ab阻断CTL向肿瘤细胞的迁移，从而显著抑制肿瘤细胞凋亡。此外，胶原和成纤维细胞分离层中的抗CCR 2抗体阻断CTL向肿瘤细胞的迁移，随后抑制肿瘤细胞凋亡。从浸润性肿瘤组织中分离的另外四名CRC患者的淋巴细胞中CCR 2的表达表明它们在其他CRC患者中的迁移中的作用。我们的数据表明，由肿瘤细胞分泌的CCL 2和CTL上的CCR 2受体参与CTL向肿瘤的迁移。用CCL 2或CCL 2/抗肿瘤Ab融合蛋白对肿瘤细胞进行基因治疗可以吸引潜在地可以抑制肿瘤生长的CTL。
Infiltration of colorectal carcinomas (CRC) with T-cells has been associated with good prognosis. There are some indications that chemokines could be involved in T-cell infiltration of tumors. Selective modulation of chemokine activity at the tumor site could attract immune cells resulting in tumor growth inhibition. In mouse tumor model systems, gene therapy with chemokines or administration of antibody (Ab)-chemokine fusion proteins have provided potent immune mediated tumor rejection which was mediated by infiltrating T cells at the tumor site. To develop such immunotherapeutic strategies for cancer patients, one must identify chemokines and their receptors involved in T-cell migration toward tumor cells. To identify chemokine and chemokine receptors involved in T-cell migration toward CRC cells, we have used our previously published three-dimensional organotypic CRC culture system. Organotypic culture was initiated with a layer of fetal fibroblast cells mixed with collagen matrix in a 24 well tissue culture plate. A layer of CRC cells was placed on top of the fibroblast-collagen layer which was followed by a separating layer of fibroblasts in collagen matrix. Anti-CRC specific cytotoxic T lymphocytes (CTLs) mixed with fibroblasts in collagen matrix were placed on top of the separating layer. Excess chemokine ligand (CCL) or Abs to chemokine or chemokine receptor (CCR) were used in migration inhibition assays to identify the chemokine and the receptor involved in CTL migration. Inclusion of excess CCL2 in T-cell layer or Ab to CCL2 in separating layer of collagen fibroblasts blocked the migration of CTLs toward tumor cells and in turn significantly inhibited tumor cell apoptosis. Also, Ab to CCR2 in the separating layer of collagen and fibroblasts blocked the migration of CTLs toward tumor cells and subsequently inhibited tumor cell apoptosis. Expression of CCR2 in four additional CRC patients' lymphocytes isolated from infiltrating tumor tissues suggests their role in migration in other CRC patients. Our data suggest that CCL2 secreted by tumor cells and CCR2 receptors on CTLs are involved in migration of CTLs towards tumor. Gene therapy of tumor cells with CCL2 or CCL2/anti-tumor Ab fusion proteins may attract CTLs that potentially could inhibit tumor growth.
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影响因子：
5.4
作者：
BINNERTS, ME;VANKOOYK, Y;FIGDOR, CG
通讯作者：
FIGDOR, CG
影响因子：
5.8
作者：
HUANG, SY;SINGH, RK;BARELI, M
通讯作者：
BARELI, M
影响因子：
46.9
作者：
Biragyn, A;Tani, K;Kwak, LW
通讯作者：
Kwak, LW
影响因子：
9
作者：
Kim, Joseph;Mori, Takuji;Hoon, Dave S. B.
通讯作者：
Hoon, Dave S. B.
影响因子：
11.2
作者：
Fushimi, T;O'Connor, TP;Crystal, RG
通讯作者：
Crystal, RG