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

摘要 自发T细胞压抗肿瘤是一种保守的抗肿瘤免疫机制 控制力。另一方面，免疫治疗旨在缓解固体内瘫痪的T细胞功能障碍 肿瘤只使一小部分转移性疾病的患者受益。这块土地迫切需要 能够增强持续的T细胞介导的对原发和慢性粒细胞白血病的控制的补充疗法的发展 转移性肿瘤生长。然而，肿瘤内的髓系细胞是克服这些障碍的主要障碍。 免疫功能障碍存在于大多数癌症中。 在这里，我们证明了通过TLR5信号识别共生细菌导致持续 髓系功能障碍和对PD-L1阻断的反应受损。TLR5信号广泛损害髓系功能， 导致T细胞功能低下的肿瘤浸润性病变。在TLR5 KO小鼠中，PD-L1阻断实现 显著提高总体存活率，并导致攻击性小鼠的持久和长期缓解 卵巢肿瘤。TLR5信号在无反应性黑色素瘤和乳腺肿瘤中的作用 模型，表明这一信号通路是免疫抑制和失败的保守机制 用于PD-L1封锁。髓系功能障碍和PD-L1阻断失败的机制在很大程度上 专注于肿瘤和免疫细胞之间的相互作用。然而，我们的数据暗示了一种机制 表达TLR5的免疫细胞识别共生细菌启动髓系功能障碍和 PD-L1阻断失败。基于这些数据，抑制TLR5信号作为恢复的一种手段出现 抗肿瘤T细胞在多种肿瘤类型中发挥作用。然而，因为TLR5信令是规范的 与其他环境中适应性免疫的激活相关，了解TLR5信号是如何 损害肿瘤微环境中的髓系功能。 首要目标是确定共生微生物如何损害抗肿瘤免疫和反应。 调到PD-L1封锁。在这里，我们将检验一种假设，即慢性接触微生物衍生的TLR5 IL-6的配体和自分泌扩增使肿瘤内表达TLR5的髓系细胞极化 微环境(TME)。这导致髓系细胞启动和/或召回肿瘤反应性T细胞的能力受损 细胞和随后失败的PD-L1阻断。目标1将定义髓系细胞上的TLR5信号如何影响 肿瘤生长和对PD-L1阻断的反应。AIM 2将确定TLR5信号如何损害髓系 功能。AIM 3将利用共生微生物的体内标记来确定 肿瘤微环境中的共生微生物和表达TLR5的免疫细胞损害抗 肿瘤免疫功能。从机理上讲，人们对微生物群如何对宿主产生负面影响知之甚少。 抗肿瘤免疫功能。本文提出的研究将填补这一知识空白，提供批判性的见解。 研究宿主-微生物组串扰如何对抗肿瘤免疫和对PD-L1阻断的反应产生负面影响。

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.