Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells.
Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells.
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DOI：
10.4049/jimmunol.181.1.808
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发表时间：
2008-07-01
期刊：
影响因子：
--
通讯作者：
Avigan D
中科院分区：
文献类型：
--
作者：
Vasir B;Wu Z;Crawford K;Rosenblatt J;Zarwan C;Bissonnette A;Kufe D;Avigan D
树突状细胞（DC）/乳腺癌融合的患者接种疫苗刺激了大多数转移性疾病患者的抗肿瘤免疫应答，但只有一个子集显示肿瘤消退的证据。为了确定限制疫苗效力的因素，我们研究了DC/乳腺癌融合物作为APC的生物学特性和疫苗介导的T细胞应答的性质。我们证明，融合的DC与乳腺癌细胞上调共刺激和成熟标志物的表达，并导致高水平的IL-12的表达与其作为活化的APC的作用一致。融合细胞还表达趋化因子受体CCR 7，这与它们迁移到引流淋巴结的能力一致。然而，DC/乳腺癌融合刺激混合T细胞应答，其特征在于活化和调节性T细胞群体的扩增，后者的特征在于CTLA-4、FOXP 3、IL-10的表达和T细胞应答的抑制。我们的研究结果表明，IL-12，IL-18和TLR 9激动剂CpG寡脱氧核苷酸降低融合介导的调节性T细胞扩增的水平。我们的研究结果还表明，连续刺激与DC/乳腺癌融合和抗CD 3/CD 28的结果在激活的肿瘤特异性T细胞的显着扩增。这些发现表明，DC/乳腺癌融合是有效的APC，但刺激抑制性T细胞，限制疫苗的功效。相反，暴露于TLR激动剂、刺激性细胞因子和抗CD 3/CD 28通过限制调节性T细胞应答和促进活化效应细胞的扩增来增强疫苗功效。
Vaccination of patients with dendritic cell (DC)/breast carcinoma fusions stimulated antitumor immune responses in a majority of patients with metastatic disease but only a subset demonstrate evidence of tumor regression. To define the factors that limit vaccine efficacy, we examined the biological characteristics of DC/breast carcinoma fusions as APCs and the nature of the vaccine-mediated T cell response. We demonstrate that fusion of DCs with breast carcinoma cells up-regulates expression of costimulatory and maturation markers and results in high levels of expression of IL-12 consistent with their role as activated APCs. Fusion cells also express the chemokine receptor CCR7, consistent with their ability to migrate to the draining lymph node. However, DC/breast cancer fusions stimulate a mixed T cell response characterized by the expansion of both activated and regulatory T cell populations, the latter of which is characterized by expression of CTLA-4, FOXP3, IL-10, and the suppression of T cell responses. Our results demonstrate that IL-12, IL-18, and TLR 9 agonist CpG oligodeoxynucleotides reduce the level of fusion-mediated regulatory T cell expansion. Our results also demonstrate that sequential stimulation with DC/breast carcinoma fusions and anti-CD3/CD28 results in the marked expansion of activated tumor-specific T cells. These findings suggest that DC/breast carcinoma fusions are effective APCs, but stimulate inhibitory T cells that limit vaccine efficacy. In contrast, exposure to TLR agonists, stimulatory cytokines, and anti-CD3/CD28 enhances vaccine efficacy by limiting the regulatory T cell response and promoting expansion of activated effector cells.
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DOI：
10.1007/s00109-006-0102-0
发表时间：
2006-12
期刊：
Journal of molecular medicine (Berlin, Germany)
影响因子：
--
作者：
Dai S;Zhou X;Wang B;Wang Q;Fu Y;Chen T;Wan T;Yu Y;Cao X
通讯作者：
Cao X
影响因子：
11.5
作者：
Avigan, D;Vasir, B;Kufe, D
通讯作者：
Kufe, D
影响因子：
15.3
作者：
Dhodapkar, M V;Steinman, R M;Krasovsky, J;Munz, C;Bhardwaj, N
通讯作者：
Bhardwaj, N
影响因子：
4.4
作者：
Bonyhadi, M;Frohlich, M;Berenson, RJ
通讯作者：
Berenson, RJ
影响因子：
3.9
作者：
Akasaki, Y;Kikuchi, T;Ohno, T
通讯作者：
Ohno, T