Effects of common polymorphisms in immune sensors in tumor immunosurveillance

描述(申请人提供)：任何TLR最常见的功能丧失是TLR5的R392X变体，它具有显性-负面效应，影响大约7%-10%的普通人群，与免疫系统的功能相关。在这里，我们将首次阐明在缺乏TLR5信号的情况下，肿瘤免疫监视机制是如何被不同地调制的。支持这一建议的主要实验发现是：1)认识到TLR5缺乏在质量和数量上都对小鼠的恶性进展提供了优越的免疫保护；2)TCGA项目的新数据分析表明，与野生型个体相比，TLR5缺乏的患者在卵巢癌诊断后两年的存活率更高；3)识别出 不同群体的γδT细胞会加速TLR5+宿主的恶性进展，但对TLR5缺乏的个体具有保护作用。基于这些和其他我们的发现， 我们的中心假设是，TLR5缺乏通过与共生微生物(鞭毛蛋白的唯一内源性来源)不同的相互作用，导致γδT细胞功能的显著差异，从而调节系统的免疫监视机制，导致对恶性进展的不同免疫保护。在目标1中，我们将确定γδT细胞如何影响野生型与TLR5缺陷型个体的肿瘤进展。这些结果将剖析在TLR5信号存在的情况下产生的γδT细胞促进肿瘤生长的抑制机制，而在TLR5缺陷宿主中产生的TLR5 T细胞则延缓肿瘤的发展。在目标2中，我们将阐明为什么γδT细胞在缺乏TLR5的荷瘤宿主中获得不同的表型。由于TLR5的配体是细菌产物，这些结果将阐明微生物区系(唯一内源性配体的载体)如何驱动γδT细胞的分化，从而决定免疫监视反应。在目标3中，我们将使用我们的活体卵巢癌和乳腺癌分离标本来确定人类TLR5缺陷和野生型癌症患者之间抗肿瘤免疫的差异。我们的工作将通过阐明相当一部分普通人群如何协调不同的抗肿瘤免疫微环境，使他们对特定的免疫治疗干预更敏感，从而在该领域产生深远的影响。此外，这项研究可能为了解数百万人如何更容易(或显示出增强的保护)患上侵袭性肿瘤，以应对其他人仍然没有症状的突变事件铺平道路。

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 γδ 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 γδ T cells, which modulate systemic mechanisms of immune surveillance, leading to different immune protection against malignant progression. In Aim 1, we will determine how γδ T cells influence tumor progression in wild-type vs. TLR5-deficient individuals. These results will dissect the suppressive mechanisms whereby γδ 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 γδ 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 γδ 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.