Tissue Microenvironment Reprograms the Circulating Memory T Cell Differentiation and Enhances Vaccine-Elicited Anti-Metastasis Immunity

Abstract

Abstract During tumor ontogeny and viral infection, heterologous subsets of CD8+ T lymphocytes provide immediate clearance and durable protection. We utilized model antigen (HIV-1-Gag) expressing melanoma cell line and parabiosis model to investigate the role of different components of memory T cells, including circulating memory T cells (T cirm) and tissue-resident memory T cells (T RM), in melanoma lung metastasis protection. We first proved that T RMgenerated by DNA vaccine intramuscular prime followed by influenza-vectored vaccine intranasal boost immunization regime mediated potent and long-lasting anti-lung metastasis immunity, whereas T cirminduced in different vaccination combinations was not capable to provide sufficient protection. To further explain the mechanism behind the potent T RMgenerated by prime-boost immunization, we found that DNA vaccination elicited a large amount of central memory T cells (T CM) in the circulation and was preferentially differentiated into lung T RMafter the intranasal booster immunization. Single-cell RNA sequencing profile illustrated the tissue microenvironment post mucosal immunization reshaped the differentiation of circulating T CMelicited by systemic immunization and enhanced the anti-metastasis T cell immunity. Thus, our research highlighted the importance of T RMin lung metastasis protection and provided insight into the mechanism of lung T RMestablishment in the prime-boost vaccination.