Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (TRM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung TRM cells can help to improve strategies, preventing tumor metastasis. Here, we found that a prime-boost vaccination approach using intramuscular DNA vaccine priming, followed by intranasal live-attenuated influenza-vectored vaccine (LAIV) boosting induced higher frequencies of lung CD8+ TRM cells compared with other vaccination regimens. Vaccine-induced lung CD8+ TRM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (TCM) cells induced by the DNA vaccination were major precursors of lung TRM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of TCM cells for differentiation into TRM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit TCM cells via CXCR3-dependent chemotaxis and induced CD8+ TRM-associated transcriptional programs. These results identified TCM cells as the source of vaccine-induced CD8+ TRM cells that protect against lung metastasis. Significance: Prime-boost vaccination shapes the mucosal microenvironment and reprograms central memory T cells to generate lung resident memory T cells that protect against lung metastasis, providing insights for the optimization of vaccine strategies.

中文翻译：

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Prime-Boost 疫苗接种方法可诱导源自中央记忆 T 细胞的肺驻留记忆 CD8+ T 细胞，从而预防肿瘤肺转移


记忆 T 细胞在癌症免疫保护中发挥着关键作用。疫苗诱导的肺部组织驻留记忆 T (TRM) 细胞已被证明可以预防肺转移。识别肺 TRM 细胞的来源有助于改进策略，预防肿瘤转移。在这里，我们发现，与其他疫苗接种方案相比，使用肌内 DNA 疫苗引发、随后鼻内减毒流感病毒载体疫苗 (LAIV) 加强的初免-加强疫苗接种方法可诱导更高频率的肺部 CD8+ TRM 细胞。疫苗诱导的肺 CD8+ TRM 细胞（但不是循环记忆 T 细胞）对转移性黑色素瘤和间皮瘤具有显着的保护作用。 DNA 疫苗接种诱导的中央记忆 T (TCM) 细胞是鼻内 LAIV 加强后建立的肺 TRM 细胞的主要前体。单细胞 RNA 测序分析表明，早在 LAIV 加强后的第 2 天，TCM 细胞的转录重编程就开始分化为肺部的 TRM 细胞。鼻内 LAIV 改变了粘膜微环境，通过 CXCR3 依赖性趋化作用招募 TCM 细胞，并诱导 CD8+ TRM 相关转录程序。这些结果确定 TCM 细胞是疫苗诱导的 CD8+ TRM 细胞的来源，可预防肺转移。意义：初免加强疫苗接种可塑造粘膜微环境，并重新编程中央记忆 T 细胞，生成可预防肺转移的肺常驻记忆 T 细胞，为优化疫苗策略提供见解。