A Prime-Boost Vaccination Approach Induces Lung Resident Memory CD8+ T Cells Derived from Central Memory T Cells That Prevent Tumor Lung Metastasis

Memory T cells play a key role in immune protection against cancer. Vaccine-induced tissue-resident memory T (T-RM) cells in the lung have been shown to protect against lung metastasis. Identifying the source of lung T-RM 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(+) T-RM cells compared with other vaccination regimens. Vaccine-induced lung CD8(+) T-RM cells, but not circulating memory T cells, conferred significant protection against metastatic melanoma and mesothelioma. Central memory T (T-CM) cells induced by the DNA vaccination were major precursors of lung T-RM cells established after the intranasal LAIV boost. Single-cell RNA sequencing analysis indicated that transcriptional reprogramming of T-CM cells for differentiation into T-RM cells in the lungs started as early as day 2 post the LAIV boost. Intranasal LAIV altered the mucosal microenvironment to recruit T-CM cells via CXCR3-dependent chemotaxis and induced CD8(+) T-RM-associated transcriptional programs. These results identified T-CM cells as the source of vaccine-induced CD8(+) T-RM 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.