Effects of common polymorphisms in immune sensors in tumor immunosurveillance

描述（由申请方提供）：任何TLR最常见的功能丧失是TLR 5的R392 X变体，其具有显性负效应，影响约7-10%的一般人群，并与免疫系统功能相关。在这里，我们将首次阐明肿瘤免疫监视机制是如何在TLR 5信号转导的情况下进行差异调节的。支持这一提议的关键实验发现是：1）认识到TLR 5缺陷在小鼠中赋予针对恶性进展的上级免疫保护，无论是在质量上还是在程度上; 2）对来自TCGA项目的新数据的分析表明，与野生型个体相比，TLR 5缺陷的患者在卵巢癌诊断两年后存活的比例更高;（3）A的识别 不同的人口？在TLR 5+宿主中加速恶性进展，但在TLR 5缺陷个体中发挥保护活性的T细胞。基于这些和我们的其他发现， 我们的中心假设是，TLR 5缺乏，通过不同的相互作用与微生物（唯一的内源性来源的鞭毛蛋白），结果在显着的功能差异？T细胞，调节免疫监视的系统机制，导致针对恶性进展的不同免疫保护。在目标1中，我们将如何确定？T细胞影响野生型与TLR 5缺陷型个体的肿瘤进展这些结果将剖析抑制机制，从而？在TLR 5信号传导存在下产生的T细胞促进肿瘤生长，而TLR 5缺陷宿主中的对应物延迟恶性发展。 在目标2中，我们将阐明为什么？T细胞在TLR 5缺陷的荷瘤宿主中获得不同的表型。由于TLR 5的配体是细菌产物，这些结果将阐明微生物群（唯一内源性配体的载体）如何驱动TLR 5的分化。决定免疫监视反应的T细胞。 在目标3中，我们将使用我们的卵巢癌和乳腺癌分离样本库，确定人类TLR 5缺陷型和野生型癌症患者之间的抗肿瘤免疫差异。 我们的工作将通过阐明普通人群中的重要部分如何协调不同的抗肿瘤免疫微环境，使其对特异性免疫干预更具反应性，从而在该领域产生深远的影响。此外，这项研究可以为理解数百万人如何更容易（或显示出增强的保护）发展为侵袭性肿瘤铺平道路，以应对在其他人中保持无症状的诱变事件。

DESCRIPTION (provided by applicant): The most frequent loss-of-function for any TLR is the R392X variant of TLR5, which has a dominant-negative effect, affects ~7-10% of the general population, and is relevant for the function of the immune system. Here, we will elucidate for the first time how mechanisms of tumor immunosurveillance are differentially modulated in the absence of TLR5 signaling. Key experimental findings supporting this proposal have been: 1) The recognition that TLR5-deficiency confers superior immune protection against malignant progression in mice, both in terms of quality and magnitude; 2) analysis of emerging data from TCGA project indicating that TLR5- deficient patients survive in higher proportions after two years of an ovarian cancer diagnosis, compared to wild-type individuals; 3) the identification of a dissimilar population of ?¿ T cells that accelerates malignant progression in TLR5+ hosts, but exerts protective activity in TLR5-deficient individuals. Based on these and other of our findings, our central hypothesis is that TLR5-deficiency, through dissimilar interactions with commensal microorganisms (the only endogenous source of flagellin), results in significant functional differences in ?¿ T cells, which modulate systemic mechanisms of immune surveillance, leading to different immune protection against malignant progression. In Aim 1, we will determine how ?¿ T cells influence tumor progression in wild-type vs. TLR5-deficient individuals. These results will dissect the suppressive mechanisms whereby ?¿ T cells generated in the presence of TLR5 signaling promote tumor growth, while their counterpart in TLR5-deficient hosts delay malignant development. In Aim 2, we will elucidate why ?¿ T cells acquire a different phenotype in TLR5-deficient tumor-bearing hosts. Because the ligand of TLR5 is a bacterial product, these results will elucidate how microbiota (carriers of the only endogenous ligand) drives the differentiation of ?¿ T cells that determine immunosurveillance responses. In Aim 3, we will define differences in anti-tumor immunity between human TLR5-deficient and wild-type cancer patients, using our bank of viable ovarian and breast cancer dissociated specimens. Our work will exert a profound effect in the field by elucidating how a significant segment of the general population may orchestrate different anti-tumor immune microenvironments that could make them more responsive to specific immunotherapeutic interventions. Furthermore, this research could pave the way for understanding how millions of individuals may be more susceptible (or show enhanced protection) to develop aggressive tumors in response to mutagenic events that remain asymptomatic in other people.