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GDNPs reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment

ABSTRACT: Lines of evidence indicate that, immune checkpoints (ICs) inhibitors enhance T cell immune response to exert anti-tumor effects. However, T cell exhaustion is still a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear. In this study, we demonstrated that GDNPs reprogramed TAMs via reducing arginase-1 (ARG1) production. Moreover, normalized arginine metabolism ameliorate T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion. Together, these results provide new insights in understanding the mechanisms involved in reversing T cell exhaustion, which may facilitate the development of new therapeutic strategy for cancer treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE241285 | GEO | 2023/12/06

REPOSITORIES: GEO

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GDNPs reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment

Project description:GDNPs reprogram macrophages to regulate arginase-1 release for ameliorating T cell exhaustion in tumor microenvironment

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Mitochondrial Arginase-2 deletion enhances the function of in vivo activated murine CD8+ T cells

Project description:As sufficient extracellular arginine is crucial for T cell function, depletion of extracellular arginine by elevated Arginase 1 (Arg1) activity has emerged as a hallmark immunosuppressive mechanism. However, the potential cell-autonomous roles of arginases in T cells have remained unexplored. Here we show that the arginase isoform expressed by T cells, the mitochondrial Arginase 2 (Arg2), is a cell-intrinsic regulator of CD8+ T cell activity. Both germ-line Arg2 deletion and adoptive transfer of Arg2-/- CD8+ T cells significantly reduced tumor growth in preclinical cancer models by enhancing CD8+ T cell activation, effector function and persistence. Transcriptomic, proteomic and high-dimensional flow cytometry characterization revealed a CD8+ T cell-intrinsic role of Arg2 in modulating T cell activation, anti-tumor cytoxicity and memory formation, independently of extracellular arginine availability. Furthermore, specific deletion of Arg2 in CD8+ T cells strongly synergized with PD-1 blockade for the control of tumor growth and animal survival. These observations coupled with the finding that pharmacologic arginase inhibition accelerates activation of ex vivo human T cells unveil Arg2 as a new therapeutic target for T cell-based cancer therapies.

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