Tumor Cell-derived HMGB1-initiated Activation of Treg

 描述（由申请人提供）：肿瘤细胞衍生的HMGB 1启动Treg的活化摘要肿瘤细胞和肿瘤微环境（TME）中的高迁移率族蛋白1（HMGB 1）与肿瘤发生和进展的标志有关，但其在肿瘤诱导的免疫抑制中的作用尚不清楚。我们发现，肿瘤细胞中HMGB 1的稳定沉默或TME中细胞外HMGB 1的特异性抑制减少了肿瘤诱导的调节性T细胞（Treg）活化，并在多种小鼠肿瘤模型中发现了自发的CD 8 T细胞依赖性抗肿瘤免疫，表明肿瘤细胞来源的HMGB 1可能触发Treg活化。此外，我们发现，肿瘤细胞来源的HMGB 1促进胸腺基质淋巴细胞生成素（TSLP）的肿瘤细胞的生产。此外，我们发现肿瘤细胞来源的HMGB 1和TSLP共同作用以调节树突状细胞（DC）以激活Treg。我们假设生长中的肿瘤细胞来源的HMGB 1作为肿瘤细胞的细胞外信号来提高TSLP，TSLP反过来与HMGB 1“合作”，以调节DC来激活Treg。我们将用两个具体目标来检验这一中心假设：1）确定HMGB 1如何提高肿瘤细胞中的TSLP 2）剖析HMGB 1如何调节DC以激活Treg这项研究将导致一个新的概念，即HMGB 1在肿瘤进展期间具有免疫抑制作用。新的发现-揭示了HMGB 1作为细胞外信号在肿瘤细胞中升高TSLP的一种先前未知的功能，并揭示了HMGB 1和TSLP通过DC在Treg激活中的创新机制联系-将促进我们对肿瘤如何诱导Treg激活的理解。

 DESCRIPTION (provided by applicant): Tumor Cell-derived HMGB1-initiated Activation of Treg Abstract High-mobility group box 1 (HMGB1) in tumor cells and the tumor microenvironment (TME) is tied to the hallmarks of tumor development and progression, but its role in tumor-induced immune suppression is unclear. We found that stable silencing of HMGB1 in tumor cells or specific inhibiting of extracellular HMGB1 in the TME reduced tumor-induced activation of regulatory T cells (Treg) and uncovered spontaneous CD8 T cell-dependent antitumor immunity in multiple murine tumor models, suggesting that tumor cell-derived HMGB1 may trigger Treg activation. Also, we found that tumor cell-derived HMGB1 promoted the production of thymic stromal lymphopoietin (TSLP) by tumor cells. Further, we found that tumor cell-derived HMGB1 and TSLP acted together to modulate dendritic cells (DC) to activate Treg. We hypothesize that growing tumor cell-derived HMGB1 acts as an extracellular signal on tumor cells to heighten TSLP, which in turn `partners' with HMGB1, to modulate DC to activate Treg. We will test this central hypothesis with 2 specific aims: 1) Define how HMGB1 heightens TSLP in tumor cells 2) Dissect how HMGB1 modulates DC to activate Treg This study will have led to a novel concept that HMGB1 is immune suppressive during tumor progression. Novel findings -- that uncover a previously unknown function of HMGB1 as an extracellular signal elevating TSLP in tumor cells and reveal an innovative mechanistic connection between HMGB1 and TSLP in Treg activation via DC -- will advance our understanding of how tumors induce Treg activation.