Reprogramming tumor-infiltrating dendritic cells for CD103+ CD8+ mucosal T-cell differentiation and breast cancer rejection.
Reprogramming tumor-infiltrating dendritic cells for CD103+ CD8+ mucosal T-cell differentiation and breast cancer rejection.
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DOI：
10.1158/2326-6066.cir-13-0217
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发表时间：
2014-05
影响因子：
10.1
通讯作者：
Palucka K
中科院分区：
文献类型：
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作者：
Wu TC;Xu K;Banchereau R;Marches F;Yu CI;Martinek J;Anguiano E;Pedroza-Gonzalez A;Snipes GJ;O'Shaughnessy J;Nishimura S;Liu YJ;Pascual V;Banchereau J;Oh S;Palucka K
我们的研究表明，乳腺癌中的肿瘤浸润树突状细胞（DC）驱动炎性T辅助2（iTh 2）细胞和促肿瘤炎症。在这里，我们表明，β-葡聚糖curdlan（dectin-1的配体）的肿瘤内递送阻断了iTh 2细胞的生成，并阻止了体内乳腺癌的进展。Curdlan通过连接dectin-1重新编程肿瘤浸润DC，使DC能够对癌症来源的胸腺基质淋巴细胞生成素（TSLP）产生抗性，产生IL 12 p70，并有利于T辅助细胞1（Th 1）的产生。通过dectin-1激活的DC，而不是TLR-7/8配体或poly IC激活的DC，诱导CD 8 + T细胞表达CD 103（αE整联蛋白），一种癌细胞E-钙粘蛋白的配体。这些粘膜CD 8 + T细胞的产生受DC衍生的整合素αvβ8和TGF-β活化以dectin-1依赖性方式调节。这些CD 103 + CD 8+粘膜T细胞在肿瘤中积累，从而在乳腺癌的人源化小鼠模型中增加癌症坏死并抑制体内癌症进展。重要的是，由重编程DC引起的CD 103 + CD 8+粘膜T细胞可以排斥已建立的癌症。因此，重编程肿瘤浸润DC代表了癌症排斥的新策略。
Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory T helper 2 (iTh2) cells and protumor inflammation. Here we show that intratumoral delivery of the β-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells, and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DC via the ligation of dectin-1, enabling the DC to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL12p70, and to favor the generation of T helper 1 (Th1) cells. DC activated via dectin-1, but not those activated with TLR-7/8 ligand or poly IC, induce CD8+ T cells to express CD103 (αE integrin), a ligand for cancer cells E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC-derived integrin αvβ8 and TGF-β activation in a dectin-1-dependent fashion. These CD103+CD8+ mucosal T cells accumulate in the tumors thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+CD8+ mucosal T cells elicited by reprogrammed DC can reject established cancer. Thus, reprogramming tumor-infiltrating DC represents a new strategy for cancer rejection.