Inhaled TLR9 Agonist Renders Lung Tumors Permissive to PD-1 Blockade by Promoting Optimal CD4+ and CD8+ T-cell Interplay
Inhaled TLR9 Agonist Renders Lung Tumors Permissive to PD-1 Blockade by Promoting Optimal CD4+ and CD8+ T-cell Interplay
复制标题
DOI：
10.1158/0008-5472.can-18-0729
复制
发表时间：
2018-09-01
期刊：
影响因子：
11.2
通讯作者：
Guiducci, Cristiana
中科院分区：
文献类型：
--
作者：
Gallotta, Marilena;Assi, Hikmat;Guiducci, Cristiana
目前批准的PD-1/ PD-L1通路抑制剂代表了肺癌治疗的重大进展，但由于缺乏预先存在的T细胞反应性，它们在大多数患者中无效。在这里，我们表明通过吸入递送的TLR 9激动剂能够引发针对免疫原性差的肺肿瘤的T细胞应答，并补充PD-1阻断的作用。吸入TLR 9激动剂可引起荷瘤肺的深度重塑，导致肿瘤附近三级淋巴结构的形成、CD 8（+）T细胞浸润至肿瘤、树突状细胞扩增和抗体产生。吸入TLR 9激动剂也增加了荷瘤肺中功能性PD-1（低）T-bet（高）效应CD 8（+）T细胞的库。通过吸入性TLR 9激动剂治疗产生的效应CD 8（+）T细胞通过PD-1阻断而被许可成为高功能性CTL，导致肺肿瘤和肺外肿瘤病变的持久排斥。响应于吸入的TLR 9而活化的CD 4（+）T细胞通过控制增殖、防止耗竭和引导最佳功能性CTL的分化在该过程中发挥关键作用。本研究描述了一种将局部TLR 9刺激应用于无法直接注射的肿瘤类型的策略，该策略可能扩大PD-1阻断剂在非小细胞肺癌中的治疗潜力。意义：这些发现表明，局部递送toll样受体9激动剂可以改变整个器官的免疫含量，并增强免疫检查点抑制的功效。http：//cancerres. aacr期刊。org/content/canres/78/17/4943/F1。大. jpg。(C)2018年AACR。
Currently approved inhibitors of the PD-1/ PD-L1 pathway represent a major advance for the treatment of lung cancers, yet they are ineffective in a majority of patients due to lack of preexisting T-cell reactivity. Here, we show that a TLR9 agonist delivered by inhalation is able to prime T-cell responses against poorly immunogenic lung tumors and to complement the effects of PD-1 blockade. Inhaled TLR9 agonist causes profound remodeling in tumor-bearing lungs, leading to the formation of tertiary lymphoid structures adjacent to the tumors, CD8(+) T-cell infiltration into the tumors, dendritic cell expansion, and antibody production. Inhalation of TLR9 agonist also increased the pool of functional PD-1(low)T-bet(high) effector CD8(+) T cells in tumor-bearing lungs. Effector CD8(+) T cells generated by inhaled TLR9 agonist treatment were licensed by PD-1 blockade to become highly functional CTLs, leading to a durable rejection of both lung tumors and tumor lesions outside the lungs. CD4(+) T cells activated in response to inhaled TLR9 play a critical role in this process by controlling the proliferation, preventing exhaustion, and guiding the differentiation of optimally functional CTLs. This study characterizes a strategy to apply localized TLR9 stimulation to a tumor type not accessible for direct injection, a strategy that may expand the therapeutic potential of PD-1 blockade in non-small cell lung cancer.Significance: These findings demonstrate that local delivery of a toll-like receptor 9 agonist can change the immune content of an entire organ and enhance the efficacy of immune checkpoint inhibition.Graphical Abstract: http://cancerres. aacrjournals. org/content/canres/78/17/4943/F1. large. jpg. (C) 2018 AACR.