TLR5 signaling as a conserved mechanism of impaired anti-tumor immunity

TLR5 信号传导作为抗肿瘤免疫受损的保守机制

• 批准号: 10188804
• 负责人: Melanie R Rutkowski
• 金额: $ 40.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10188804
• 关键词: Ablation; Address; Affect; Anatomy; Animals; Bacteria; Breast Cancer Model; Breast Melanoma; Cell physiology; Cells; Chronic; Complementary therapies; Data; Dendritic Cells; Development; Disease; Disease remission; Failure; Foundations; Functional disorder; Gene Expression; Goals; Immune; Immune System Diseases; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infiltration; Interleukin-12; Interleukin-6; Intrinsic factor; Knockout Mice; Knowledge; Label; Lead; Leaky Gut; Ligands; Malignant Neoplasms; Mediating; Metabolic; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Outcome; Ovarian; PD-L1 blockade; Paralysed; Pathologic; Patients; Peptidoglycan; Phenotype; Primary Neoplasm; Production; Recurrence; Reporter; Repression; Research; Resistance; Role; Signal Pathway; Signal Transduction; Solid; Solid Neoplasm; T-Lymphocyte; TLR5 gene; Testing; Treatment Efficacy; Tumor Escape; Tumor Immunity; Tumor stage; Tumor-associated macrophages; Tumor-infiltrating immune cells; Wild Type Mouse; adaptive immunity; autocrine; base; cancer type; commensal bacteria; cytokine; exhaustion; host microbiome; immune function; immune resistance; in vivo; inhibitor/antagonist; insight; macrophage; melanoma; microbiome; microorganism; neoplastic cell; novel therapeutics; ovarian neoplasm; pressure; response; therapeutic evaluation; therapy development; tumor; tumor growth; tumor microenvironment; tumor progression

ABSTRACT Spontaneous T cell pressure against an evolving tumor is a conserved mechanism of anti-tumor immune control. On the other hand, immune therapies directed to alleviate paralyzing T cell dysfunction within solid tumors only benefits a small proportion of patients with metastatic disease. The field is in desperate need for the development of complementary therapies capable of enhancing sustained T cell-mediated control of primary and metastatic tumor growth. However, myeloid cells within tumors present a substantial barrier towards overcoming the immune dysfunction present in most cancers. Here, we demonstrate that recognition of commensal bacteria through TLR5 signaling results in sustained myeloid dysfunction and impaired response to PD-L1 blockade. TLR5 signaling broadly impairs myeloid function, resulting in infiltration of tumors with poorly functional T cells. In TLR5 KO mice, PD-L1 blockade achieves significantly increased overall survival and leads to durable and long-term remission for mice bearing aggressive ovarian tumors. The effect of TLR5 signaling is recapitulated in non-responsive melanoma and breast tumor models, suggesting that this signaling pathway is a conserved mechanism of immune suppression and failure for PD-L1 blockade. Mechanisms underlying myeloid dysfunction and failure of PD-L1 blockade have largely focused upon interactions between tumors and immune cells. However, our data implicate a mechanism whereby recognition of commensal bacteria by TLR5-expressing immune cells initiates myeloid dysfunction and failure of PD-L1 blockade. Based upon these data, inhibition of TLR5 signaling emerges as a means of restoring anti-tumor T cell function across a broad range of tumor types. However, because TLR5 signaling is canonically associated with activation of adaptive immunity in other settings, it is critical to understand how TLR5 signaling impairs myeloid function within the tumor microenvironment. The overarching goal is to define how commensal microorganisms impair anti-tumor immunity and response to PD-L1 blockade. Here, we will test the hypothesis that chronic encounter with microbiome-derived TLR5 ligands and autocrine amplification of IL-6 polarize TLR5-expressing myeloid cells within the tumor microenvironment (TME). This results in impaired ability of myeloid cells to prime and/or recall tumor-reactive T cells and subsequent failure of PD-L1 blockade. Aim 1 will define how TLR5 signaling on myeloid cells affects tumor growth and response to PD-L1 blockade. Aim 2 will determine how TLR5 signaling impairs myeloid function. Aim 3 will leverage in vivo labelling of commensal microorganisms to establish how encounters between commensal microorganisms and TLR5 expressing immune cells within the tumor microenvironment impair anti- tumor immune function. Mechanistically, very little is known as to how the microbiome negatively impacts host anti-tumor immune function. The studies proposed herein will fill this gap in knowledge, providing critical insight into how host-microbiome crosstalk negatively impacts anti-tumor immunity and response to PD-L1 blockade.

抽象的 自发T细胞压力针对不断发展的肿瘤是一种保守的抗肿瘤免疫机制 控制。另一方面，针对固体内部瘫痪的T细胞功能障碍的免疫疗法 肿瘤仅受益于少数转移性疾病的患者。该领域迫切需要 开发能够增强持续T细胞介导的原发性控制和 转移性肿瘤生长。但是，肿瘤中的髓样细胞具有克服的重大障碍 大多数癌症中存在免疫功能障碍。 在这里，我们证明了通过TLR5信号对共生细菌的识别导致持续 粒细胞功能障碍和对PD-L1封锁的反应受损。 TLR5信号广泛损害髓样功能， 导致功能较差的T细胞肿瘤浸润。在TLR5 KO小鼠中，PD-L1封锁成就 显着提高了总体存活率，并导致具有侵略性的小鼠的持久和长期缓解 卵巢肿瘤。 TLR5信号传导的作用在无反应性黑色素瘤和乳腺肿瘤中概括 模型，表明该信号通路是免疫抑制和失效的保守机制 对于PD-L1封锁。髓样功能障碍和PD-L1封锁失败的机制在很大程度上具有 着眼于肿瘤与免疫细胞之间的相互作用。但是，我们的数据暗示了一种机制 因此，通过表达TLR5的免疫细胞对共生细菌的识别会引起髓样功能障碍和 PD-L1封锁的故障。基于这些数据，抑制TLR5信号传导是一种恢复的手段 在广泛的肿瘤类型中的抗肿瘤T细胞功能。但是，因为TLR5信令是规范的 与其他设置中的自适应免疫激活相关，了解TLR5信号如何传导至关重要 损害肿瘤微环境中的髓样功能。 总体目标是定义共生微生物如何损害抗肿瘤的免疫和反应 到PD-L1封锁。在这里，我们将检验以下假设，即慢性遇到微生物组衍生的TLR5 IL-6的配体和自分泌扩增在肿瘤内偏振TLR5的髓样细胞 微环境（TME）。这会导致髓样细胞促进和/或回忆肿瘤反应性T的能力受损 细胞和随后的PD-L1阻滞失败。 AIM 1将定义髓样细胞上的TLR5信号传导如何影响 肿瘤的生长和对PD-L1阻滞的反应。 AIM 2将确定TLR5信号如何损害髓样 功能。 AIM 3将利用共生微生物的体内标签来确定如何在 在肿瘤微环境中表达免疫细胞的共生微生物和TLR5损害抗抗菌 肿瘤免疫功能。从机械上讲，微生物组如何对主机产生负面影响很少知道 抗肿瘤免疫功能。本文提出的研究将在知识中填补这一空白，提供关键的见解 宿主 - 微生物组串扰如何对抗肿瘤免疫产生负面影响和对PD-L1阻滞的反应。