OV therapy induced changes in tumor secretome and their impact on therapy

描述（由申请人提供）：本提案的最终目标是评估溶瘤病毒（OV）治疗后肿瘤微环境的变化，并评估这些变化如何影响OV治疗。这些结果将有助于更好地理解OV治疗诱导的肿瘤生物学变化。肿瘤的OV治疗依赖于病毒的癌症特异性复制，导致肿瘤破坏，对邻近非肿瘤组织的毒性最小。临床试验结果表明，使用具有复制能力的OVs治疗恶性胶质瘤患者的新模式相对安全，但对疗效的高期望仍未达到（1,2）。肿瘤的微环境越来越被认为是其进展及其对治疗反应的重要决定因素。我们正在研究溶瘤病毒（OV）治疗后肿瘤微环境的变化，最终目标是设计更好的治疗策略来对抗脑肿瘤。在我们的初步研究中，我们发现HMGB1的释放显著增加。HMGB1通常是一种细胞蛋白，在某些刺激下释放到细胞外环境中，并可作为损伤相关的分子模式。在本研究中，我们将评估这种细胞外HMGB1对肿瘤微环境的影响，它对内皮细胞（Aim 1）、巨噬细胞（Aim 2）和抗原向T细胞递呈（Aim 3）的影响。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to evaluate the changes induced in the tumor microenvironment upon treatment with oncolytic viruses (OV) and assess how these changes impact OV therapy. These results will lead to a better understanding of OV therapy induced changes in tumor biology. OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent no- neoplastic tissue. Results from clinical trials using replication competent OVs to treat patients with malignant gliomas have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. We are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. In our preliminary studies, we have uncovered a significant increase in the release of HMGB1. HMGB1 is normally a cellular protein which is released into the extracellular environment upon certain stimuli and can serve as a damage associated molecular pattern. In this study we will evaluate the impact of this extracellular HMGB1 on tumor microenvironment, its impact on endothelial cells (Aim 1), macrophages (Aim 2) and antigen presentation to T cells (Aim 3).