Accumulation of CCR4⁺CTLA-4 FOXP3⁺CD25(hi) regulatory T cells in colon adenocarcinomas correlate to reduced activation of conventional T cells.
Accumulation of CCR4⁺CTLA-4 FOXP3⁺CD25(hi) regulatory T cells in colon adenocarcinomas correlate to reduced activation of conventional T cells.
复制标题
结肠腺癌中CCR4⁺CTLA-4FOXP3⁺CD25（HI）调节性T细胞与常规T细胞的激活相关。
DOI：
10.1371/journal.pone.0030695
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Quiding-Järbrink M
中科院分区：
文献类型：
--
作者：
Svensson H;Olofsson V;Lundin S;Yakkala C;Björck S;Börjesson L;Gustavsson B;Quiding-Järbrink M
结直肠癌通常会产生一种特异性的抗肿瘤免疫反应，但由于未知的原因，由此产生的免疫反应不能清除肿瘤。激活的效应淋巴细胞在肿瘤中的募集对于有效的抗肿瘤反应是重要的，而调节性T细胞(Treg)的存在下调了肿瘤的特异性免疫。因此，我们的目标是在结肠腺癌患者中，与未受影响的粘膜细胞相比，确定Treg和效应器T细胞在结肠肿瘤中的归巢机制和激活阶段。采用流式细胞术、免疫组织化学和定量聚合酶链式反应等方法，对浸润性Treg淋巴细胞和普通淋巴细胞的归巢机制和活化阶段进行了研究。我们检测到肿瘤中CD25HighFOXP3+CD127低可能的Treg的频率显著高于未受影响的粘膜，后者在FOXP3启动子中完全去甲基化。肿瘤相关树突状细胞高表达CTLA4，部分肿瘤相关树突状细胞表达αEβ7(CD103)，可能是抗原敏感的效应/记忆细胞。在与肿瘤相关的粘膜中，对免疫调节敏感的活化T细胞也明显减少，而CTLA-4+常规T细胞明显增加。相反，CD8+颗粒酶B+可能的细胞毒细胞被有效地招募到肿瘤中。肿瘤组织中α-4、β-7和Th1相关趋化因子受体CXCR3的表达频率显著降低，而CD_4+CCR_4+淋巴细胞的表达频率显著升高。本研究表明CCR4+CTLA4hi Treg在结肠肿瘤中积聚，而激活的传统Th1型T细胞的频率降低。结肠肿瘤中淋巴细胞成分的改变可能会降低免疫系统有效攻击肿瘤细胞的能力，降低Treg活性是未来免疫治疗方案的重要挑战。
Colorectal cancer usually gives rise to a specific anti-tumor immune response, but for unknown reasons the resulting immunity is not able to clear the tumor. Recruitment of activated effector lymphocytes to the tumor is important for efficient anti-tumor responses, while the presence of regulatory T cells (Treg) down-modulate tumor-specific immunity. We therefore aimed to determine homing mechanisms and activation stage of Treg and effector T cell infiltrating colon tumors compared to cells from the unaffected mucosa in patients suffering from colon adenocarcinoma. Lymphocytes were isolated from unaffected and tumor mucosa from patients with colon adenocarcinoma, and flow cytometry, immunohistochemistry, and quantitative PCR was used to investigate the homing mechanisms and activation stage of infiltrating Treg and conventional lymphocytes. We detected significantly higher frequencies of CD25highFOXP3+CD127low putative Treg in tumors than unaffected mucosa, which had a complete demethylation in the FOXP3 promotor. Tumor-associated Treg had a high expression of CTLA-4, and some appeared to be antigen experienced effector/memory cells based on their expression of αEβ7 (CD103). There were also significantly fewer activated T cells and more CTLA-4+ conventional T cells susceptible to immune regulation in the tumor-associated mucosa. In contrast, CD8+granzyme B+ putative cytotoxic cells were efficiently recruited to the tumors. The frequencies of cells expressing α4β7 and the Th1 associated chemokine receptor CXCR3 were significantly decreased among CD4+ T cells in the tumor, while frequencies of CD4+CCR4+ lymphocytes were significantly increased. This study shows that CCR4+CTLA4hi Treg accumulate in colon tumors, while the frequencies of activated conventional Th1 type T cells are decreased. The altered lymphocyte composition in colon tumors will probably diminish the ability of the immune system to effectively attack tumor cells, and reducing the Treg activity is an important challenge for future immunotherapy protocols.
登录
查看更多内容
DOI：
10.1084/jem.188.12.2357
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hung K;Hayashi R;Lafond-Walker A;Lowenstein C;Pardoll D;Levitsky H
通讯作者：
Levitsky H
CD127表达与FOXP3和人类CD4+ T Reg细胞的抑制功能成反比。
DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1084/jem.194.6.847
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iellem A;Mariani M;Lang R;Recalde H;Panina-Bordignon P;Sinigaglia F;D'Ambrosio D
通讯作者：
D'Ambrosio D
DOI：
10.1097/cji.0b013e3181d32f01
发表时间：
2010-05
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Correale P;Rotundo MS;Del Vecchio MT;Remondo C;Migali C;Ginanneschi C;Tsang KY;Licchetta A;Mannucci S;Loiacono L;Tassone P;Francini G;Tagliaferri P
通讯作者：
Tagliaferri P
影响因子：
4.4
作者：
Christensen, Jeanette Erbo;de Lemos, Carina;Thomsen, Allan Randrup
通讯作者：
Thomsen, Allan Randrup