Lin et al. engineered a spleen-targeted neoantigen mRNA vaccine (STNvac) using a two-component LNP formulation that selectively delivered mRNA to splenic DCs and prompted robust neoantigen-specific CD8+ T cell response in an orthotopic Hepa1-6 HCC model. STNvac induced a distinct ISG15+ CD8+ T cell subset with enhanced cytotoxicity that mediated antigen-specific tumor clearance. Single-cell and spatial analyses showed interaction between ISG15+ CD8+ T cells and intratumoral APCs via a GZMA–F2R axis, which drove ISG15+ CD8+ T cell activation, proliferation, and organization into TLSs in human and mouse HCC specimens.
Contributed by Shishir Pant
ABSTRACT: The efficacy of neoantigen vaccine for advanced hepatocellular carcinoma (HCC) is limited largely due to insufficient T cell mobilization and activation. Herein, we develop a spleen-targeted neoantigen mRNA vaccine (STNvac) with highly efficient spleen-selective mRNA transfection. Using a three-dose vaccination regimen, STNvac demonstrates remarkable therapeutic efficacy in orthotopic HCC model with a high likelihood of complete tumor regression and significantly improved survival rates (p < 0.0001). Notably, we identify a distinct ISG15(+) CD8(+) T cell population as crucial mediators of STNvac-induced immunity with potent antigen-processing and cytotoxic capacities. Intriguingly, STNvac promotes the formation of tertiary lymphoid structures (TLSs) through GZMA-F2R-mediated interactions between ISG15(+) CD8(+) T cells and antigen-presenting cells (APCs), which is also confirmed in HCC patients. Taken together, our findings demonstrate the potent antitumor efficacy of spleen-targeted mRNA vaccine and reveal its underlying immune cell interactive mechanisms, presenting high potential for clinical translation.
Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 35000
Author Info: (1) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (2) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (3) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (4) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (5) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (6) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (7) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (8) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (9) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (10) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (11) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. (12) State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. (13) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: caizhixiong1985@163.com. (14) The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350007, P.R. China; Mengchao Med-X Center, Fuzhou University, Fuzhou, Fujian 350116, P.R. China; The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, Fujian 350007, P.R. China. Electronic address: xiaoloong.liu@gmail.com.
