TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells
TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells
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TLR4 对于树突状细胞激活和化学应激癌细胞释放的 DAMP 增强抗肿瘤 T 细胞反应至关重要
DOI：
10.1038/cmi.2013.59
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发表时间：
2014-03-01
影响因子：
24.1
通讯作者：
Wan, Tao
中科院分区：
文献类型：
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作者：
Fang, Hongliang;Ang, Bing;Wan, Tao
免疫疗法和化学疗法的组合被认为是治疗某些类型癌症的有前途的方法。然而，需要充分研究潜在的机制，以指导设计更有效的癌症化学免疫治疗方案。众所周知，肿瘤相关分子模式（DAMP）可以通过Toll样受体（TLR）激活免疫细胞，包括树突状细胞（DC）;然而，从化学药物处理的肿瘤细胞释放的DAMP在免疫应答激活中的作用需要进一步阐明。在这里，我们发现用奥沙利铂（OXA）和/或5-氟尿嘧啶（5-Fu）处理的结直肠癌（CRC）细胞释放高水平的高迁移率族蛋白1（HMGB 1）和热休克蛋白70（HSP 70）。OXA/5-Fu治疗后，CRC患者血清中HMGB 1和HSP 70水平也升高，这两种蛋白都是众所周知的DAMP。OXA/5-Fu处理的死亡CRC细胞上清液促进小鼠和人DC成熟，上调HLA-DR、CD 80和CD 86表达，增加IL-1β、TNF-α、MIP-1α、MIP-1β、RANTES和IP-10的产生。用化学应激的CRC细胞上清液冲激的DC组成的疫苗在体外和体内均诱导更显著的产生IFN-γ的Th 1应答。然而，化学应激CRC细胞的上清液未能诱导TLR 4缺陷型DC中的表型成熟和细胞因子产生，表明TLR 4在DAMP诱导的DC成熟和活化中起重要作用。此外，用化学应激的CRC细胞的上清液脉冲不能有效地诱导TLR 4缺陷型DC中产生IFN-γ的Th 1应答。总的来说，这些结果表明，从化学应激的癌细胞释放的DAMP可以通过TLR 4激活DC并增强抗肿瘤T细胞免疫应答的诱导，描绘了由DAMP触发的临床相关免疫佐剂途径。
The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns (DAMPs) can activate immune cells, including dendritic cells (DCs), via Toll-like receptors (TLRs); however, the role of DAMPs released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer (CRC) cells treated with oxaliplatin (OXA) and/or 5-fluorouracil (5-Fu) released high levels of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known DAMPs. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-1β, TNF-α, MIP-1α, MIP-1β, RANTES and IP-10 production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-γ-producing Th1 response both in vitro and in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-γ-producing Th1 response in TLR4-deficient DCs. Collectively, these results demonstrate that DAMPs released from chemically stressed cancer cells can activate DCs via TLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by DAMPs.